11-62613611-TGGGGGGG-TGGGGGGGG

Variant names:

• chr11-62613611-T-TG
• rs71458427
• NM_000327.4:c.339dupG

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

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). 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:4 B:2
• Conservation: PhyloP100: 1.35

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]

ACMG classification

Verdict is Likely_benign. Variant got -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 id is 12998.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=3}.
• BS2: High Homozygotes in GnomAdExome4 at 2 Digenic gene

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000843 AC: 127 AN: 150732 Hom.: 1 Cov.: 34

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

GnomAD4 exome AF: 0.000709 AC: 1011 AN: 1425960 Hom.: 2 Cov.: 77 AF XY: 0.000743 AC XY: 527 AN XY: 709354

Gnomad4 AFR exome AF: 0.00226

Gnomad4 AMR exome AF: 0.000321

Gnomad4 ASJ exome AF: 0.00121

Gnomad4 EAS exome AF: 0.00301

Gnomad4 SAS exome AF: 0.00107

Gnomad4 FIN exome AF: 0.00380

Gnomad4 NFE exome AF: 0.000395

Gnomad4 OTH exome AF: 0.00102

GnomAD4 genome AF: 0.000822 AC: 124 AN: 150848 Hom.: 0 Cov.: 34 AF XY: 0.000801 AC XY: 59 AN XY: 73668

Gnomad4 AFR AF: 0.00119

Gnomad4 AMR AF: 0.000396

Gnomad4 ASJ AF: 0.00116

Gnomad4 EAS AF: 0.00409

Gnomad4 SAS AF: 0.00212

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000474

Gnomad4 OTH AF: 0.000968

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Retinitis pigmentosa Pathogenic:1 Uncertain: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:1 Benign:1

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal dystrophy Uncertain:1 Benign: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

- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs71458427; hg19: chr11-62381083;