11-62613611-TGGGGGGG-TGGGGGGGG

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_000327.4(ROM1):c.339dupG(p.Leu114AlafsTer18) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00072 in 1,576,808 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L114L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00082 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00071 ( 2 hom. )

Consequence

ROM1
NM_000327.4 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:4B:3

Conservation

PhyloP100: 1.35

Publications

14 publications found

Variant links:

Genes affected

ROM1 (HGNC:10254): (retinal outer segment membrane protein 1) This gene is a member of a photoreceptor-specific gene family and encodes an integral membrane protein found in the photoreceptor disk rim of the eye. This protein can form homodimers or can heterodimerize with another photoreceptor, retinal degeneration slow (RDS). It is essential for disk morphogenesis, and may also function as an adhesion molecule involved in the stabilization and compaction of outer segment disks or in the maintenance of the curvature of the rim. Certain defects in this gene have been associated with the degenerative eye disease retinitis pigmentosa. [provided by RefSeq, Jul 2008]

ROM1 Gene-Disease associations (from GenCC):

retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
retinitis pigmentosa 7
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ROM1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP6

Variant 11-62613611-T-TG is Benign according to our data. Variant chr11-62613611-T-TG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 12998.

BS2

High AC in GnomAd4 at 124 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROM1	NM_000327.4 link	c.339dupG	p.Leu114AlafsTer18	frameshift_variant	Exon 1 of 3	ENST00000278833.4	NP_000318.2	Q03395

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ROM1	ENST00000278833.4 link	c.339dupG	p.Leu114AlafsTer18	frameshift_variant	Exon 1 of 3	1	NM_000327.4	ENSP00000278833.3	Q03395
ROM1	ENST00000525947.1 link	c.-194dupG		5_prime_UTR_variant	Exon 1 of 3	3		ENSP00000432983.1	E9PMR7
ROM1	ENST00000534093.5 link	c.-38-638dupG		intron_variant	Intron 1 of 2	2		ENSP00000432151.1	E9PS24
ROM1	ENST00000525801.1 link	c.-38-638dupG		intron_variant	Intron 1 of 1	3		ENSP00000433566.1	E9PKF5

Frequencies

GnomAD3 genomes

AF:

0.000843

AC:

127

AN:

150732

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00120

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000396

Gnomad ASJ

AF:

0.00116

Gnomad EAS

AF:

0.00467

Gnomad SAS

AF:

0.00212

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000474

Gnomad OTH

AF:

0.000978

GnomAD2 exomes

AF:

0.00140

AC:

300

AN:

214556

AF XY:

0.00115

show subpopulations

Gnomad AFR exome

AF:

0.00205

Gnomad AMR exome

AF:

0.000348

Gnomad ASJ exome

AF:

0.00155

Gnomad EAS exome

AF:

0.00520

Gnomad FIN exome

AF:

0.000611

Gnomad NFE exome

AF:

0.00119

Gnomad OTH exome

AF:

0.000559

GnomAD4 exome

AF:

0.000709

AC:

1011

AN:

1425960

Hom.:

Cov.:

AF XY:

0.000743

AC XY:

527

AN XY:

709354

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00226

AC:

AN:

32744

American (AMR)

AF:

0.000321

AC:

AN:

43600

Ashkenazi Jewish (ASJ)

AF:

0.00121

AC:

AN:

25660

East Asian (EAS)

AF:

0.00301

AC:

117

AN:

38892

South Asian (SAS)

AF:

0.00107

AC:

AN:

84972

European-Finnish (FIN)

AF:

0.00380

AC:

189

AN:

49752

Middle Eastern (MID)

AF:

0.00107

AC:

AN:

5626

European-Non Finnish (NFE)

AF:

0.000395

AC:

429

AN:

1085648

Other (OTH)

AF:

0.00102

AC:

AN:

59066

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.390

Heterozygous variant carriers

108

163

217

271

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000822

AC:

124

AN:

150848

Hom.:

Cov.:

AF XY:

0.000801

AC XY:

AN XY:

73668

show subpopulations

African (AFR)

AF:

0.00119

AC:

AN:

41100

American (AMR)

AF:

0.000396

AC:

AN:

15154

Ashkenazi Jewish (ASJ)

AF:

0.00116

AC:

AN:

3458

East Asian (EAS)

AF:

0.00409

AC:

AN:

5130

South Asian (SAS)

AF:

0.00212

AC:

AN:

4718

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10470

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000474

AC:

AN:

67550

Other (OTH)

AF:

0.000968

AC:

AN:

2066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00152

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:4Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Retinitis pigmentosa

Pathogenic:1Uncertain:1

Department of Ophthalmology and Visual Sciences Kyoto University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Aug 19, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP5. -

not provided

Uncertain:1Benign:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal dystrophy

Uncertain:1Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Jan 01, 2023

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Retinitis pigmentosa 7, digenic

Pathogenic:1

Jun 10, 1994

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

ROM1-related disorder

Pathogenic:1

May 24, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ROM1 c.339dupG variant is predicted to result in a frameshift and premature protein termination (p.Leu114Alafs*18). This variant, in the heterozygous state, along with a PRPH2 c.554T>C (p.Leu185Pro) variant, has been reported to be causative for digenic retinitis pigmentosa (Sullivan. 2006. PubMed ID: 16799052, Table 3; Kajiwara et al. 1994. PubMed ID: 8202715, families #6285, #6935 and #5509; Dryja et al. 1997. PubMed ID: 9331261, family #0782). Kajiwara et al. showed that the individuals who are heterozygous carriers for either PRPH2 c.554T>C or ROM1 c.339dup were asymptomatic and affected patients were combined heterozygotes for PRPH2 and ROM1 variants. Mouse model studies also supported the digenic inheritance of RP (Kedzierski et al. 2001. PubMed ID: 11427722). Of note, protein truncating variants surrounding this region have been documented in individuals with autosomal dominant and digenic forms of retinal disorders (Zernant et al. 2022. PubMed ID: 35353811; Panneman et al. 2023. PubMed ID: 36819107). This variant is reported in 0.52% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as likely pathogenic. -

Retinitis pigmentosa 7

Uncertain:1

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

May 27, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ROM1 c.339dupG (p.Leu114AlafsX18) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, however current evidence is not sufficient to establish loss of function as a mechanism for disease. The variant allele was found at a frequency of 0.00072 in 1576808 control chromosomes, predominantly at a frequency of 0.0031 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in ROM1 causing Retinitis Pigmentosa 7 phenotype. c.339dupG has been observed in individuals affected with Retinitis Pigmentosa or other inhertied retinal diseases (e.g., Kajiwara_1994, Bascom_1995, Yohe_2020, Panneman_2023, Hitti-Malin_2024). These reports do not provide unequivocal conclusions about association of the variant with Retinitis Pigmentosa 7. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 8202715, 31816670, 36819107, 8595413, 38540785). ClinVar contains an entry for this variant (Variation ID: 12998). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.4

Mutation Taster

=13/187

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over