rs146358003

Variant names:

• chr11-62613604-C-T
• rs146358003
• NM_000327.4:c.323C>T
• ROM1 p.Thr108Met

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000327.4(ROM1):​c.323C>T​(p.Thr108Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000396 in 1,612,238 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T108T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00057 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00038 (1 hom.)
• Consequence: ROM1 NM_000327.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.14
• Publications: 12 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: Unknown, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.035583228).
• BS2: High AC in GnomAd4 at 87 AD,Unknown 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.323C>T	p.Thr108Met	missense	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.323C>T	p.Thr108Met	missense	Exon 1 of 3	ENSP00000278833.3	Q03395
	ROM1	ENST00000525947.1	TSL:3	c.-210C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	ENSP00000432983.1	E9PMR7
	ROM1	ENST00000525947.1	TSL:3	c.-210C>T		5_prime_UTR	Exon 1 of 3	ENSP00000432983.1	E9PMR7

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152092 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000471

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000268 AC: 65 AN: 242678 AF XY: 0.000226

Gnomad AFR exome AF: 0.0000689

Gnomad AMR exome AF: 0.000408

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000549

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000406

Gnomad OTH exome AF: 0.000842

GnomAD4 exome AF: 0.000378 AC: 552 AN: 1460026 Hom.: 1 Cov.: 77 AF XY: 0.000322 AC XY: 234 AN XY: 726240

African (AFR) AF: 0.000179 AC: 6 AN: 33460

American (AMR) AF: 0.000896 AC: 40 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 86042

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52708

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.000422 AC: 469 AN: 1111430

Other (OTH) AF: 0.000564 AC: 34 AN: 60234

GnomAD4 genome AF: 0.000572 AC: 87 AN: 152212 Hom.: 1 Cov.: 34 AF XY: 0.000578 AC XY: 43 AN XY: 74432

African (AFR) AF: 0.000361 AC: 15 AN: 41536

American (AMR) AF: 0.00229 AC: 35 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000471 AC: 32 AN: 67996

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00227 Hom.: 1

Bravo AF: 0.000910

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.000273

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.021
Eigen_PC	Benign	-0.018
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.036	T
MetaSVM	Uncertain	-0.094	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.1
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.21	N
REVEL	Uncertain	0.38
Sift	Benign	0.082	T
Sift4G	Benign	0.11	T
PromoterAI		0.013	Neutral
Varity_R		0.045
gMVP		0.51
Mutation Taster		=91/9	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs146358003;

hg19: chr11-62381076;