NM_000327.4:c.339dupG

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -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). 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:4 B:3
• Conservation: PhyloP100: 1.35
• Publications: 14 publications found

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 7

  Inheritance: AD, Unknown Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000327.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROM1	NM_000327.4	MANE Select	c.339dupG	p.Leu114AlafsTer18	frameshift	Exon 1 of 3	NP_000318.2	Q03395

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROM1	ENST00000278833.4	TSL:1 MANE Select	c.339dupG	p.Leu114AlafsTer18	frameshift	Exon 1 of 3	ENSP00000278833.3	Q03395
	ROM1	ENST00000525947.1	TSL:3	c.-194dupG		5_prime_UTR	Exon 1 of 3	ENSP00000432983.1	E9PMR7
	ROM1	ENST00000534093.5	TSL:2	c.-38-638dupG		intron	N/A	ENSP00000432151.1	E9PS24

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

GnomAD2 exomes AF: 0.00140 AC: 300 AN: 214556 AF XY: 0.00115

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.: 2 Cov.: 77 AF XY: 0.000743 AC XY: 527 AN XY: 709354

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

African (AFR) AF: 0.00226 AC: 74 AN: 32744

American (AMR) AF: 0.000321 AC: 14 AN: 43600

Ashkenazi Jewish (ASJ) AF: 0.00121 AC: 31 AN: 25660

East Asian (EAS) AF: 0.00301 AC: 117 AN: 38892

South Asian (SAS) AF: 0.00107 AC: 91 AN: 84972

European-Finnish (FIN) AF: 0.00380 AC: 189 AN: 49752

Middle Eastern (MID) AF: 0.00107 AC: 6 AN: 5626

European-Non Finnish (NFE) AF: 0.000395 AC: 429 AN: 1085648

Other (OTH) AF: 0.00102 AC: 60 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.

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

African (AFR) AF: 0.00119 AC: 49 AN: 41100

American (AMR) AF: 0.000396 AC: 6 AN: 15154

Ashkenazi Jewish (ASJ) AF: 0.00116 AC: 4 AN: 3458

East Asian (EAS) AF: 0.00409 AC: 21 AN: 5130

South Asian (SAS) AF: 0.00212 AC: 10 AN: 4718

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10470

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000474 AC: 32 AN: 67550

Other (OTH) AF: 0.000968 AC: 2 AN: 2066

Alfa AF: 0.00152 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	1	Retinal dystrophy (2)
1	1	-	Retinitis pigmentosa (2)
-	-	1	not specified (1)
-	1	-	Retinitis pigmentosa 7 (1)
1	-	-	Retinitis pigmentosa 7, digenic (1)
1	-	-	ROM1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
Mutation Taster		=13/187	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs71458427; hg19: chr11-62381083; COSMIC: COSV53881661; COSMIC: COSV53881661;