rs150168119

chr11-62614353-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000327.4(ROM1):c.686G>A(p.Arg229His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00279 in 1,614,002 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R229C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0036 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (26 hom.)
• Consequence: ROM1 NM_000327.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.705

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042440295).
• BP6: Variant 11-62614353-G-A is Benign according to our data. Variant chr11-62614353-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 195064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-62614353-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 3 Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ROM1	NM_000327.4	c.686G>A	p.Arg229His	missense_variant	2/3	ENST00000278833.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROM1	ENST00000278833.4	c.686G>A	p.Arg229His	missense_variant	2/3	1	NM_000327.4	P1
ROM1	ENST00000534093.5	c.58G>A	p.Val20Ile	missense_variant	2/3	2
ROM1	ENST00000525947.1	c.58G>A	p.Val20Ile	missense_variant	2/3	3
ROM1	ENST00000525801.1	c.58G>A	p.Val20Ile	missense_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.00358 AC: 544 AN: 152008 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00547

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00344 AC: 864 AN: 251468 Hom.: 3 AF XY: 0.00337 AC XY: 458 AN XY: 135914

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00327

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0122

Gnomad NFE exome AF: 0.00473

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00270 AC: 3951 AN: 1461876 Hom.: 26 Cov.: 33 AF XY: 0.00287 AC XY: 2088 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00333

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0109

Gnomad4 NFE exome AF: 0.00282

Gnomad4 OTH exome AF: 0.00210

GnomAD4 genome AF: 0.00358 AC: 544 AN: 152126 Hom.: 3 Cov.: 33 AF XY: 0.00403 AC XY: 300 AN XY: 74368

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0132

Gnomad4 NFE AF: 0.00547

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00465 Hom.: 3

Bravo AF: 0.00205

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00477 AC: 41

ExAC AF: 0.00366 AC: 444

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00453

EpiControl AF: 0.00237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	ROM1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 31, 2014

- -

Larsen-like syndrome, B3GAT3 type Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 20, 2020

- -

Retinitis pigmentosa Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	13
Dann	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.060	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.60	N
REVEL	Benign	0.18
Sift	Benign	0.22	T
Sift4G	Benign	0.18	T
Polyphen		0.048	B
Vest4		0.076
MVP		0.15
MPC		0.058
ClinPred		0.012	T
GERP RS		-2.4
Varity_R		0.027
gMVP		0.47

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: rs150168119; hg19: chr11-62381825;