NM_022369.4:c.1903G>A

Variant names:

• chr15-74180181-C-T
• rs145614612
• NM_022369.4:c.1903G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022369.4(STRA6):​c.1903G>A​(p.Gly635Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,613,962 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (8 hom., cov: 33)
  • Exomes 𝑓: 0.011 (106 hom.)
• Consequence: STRA6 NM_022369.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.683
• Publications: 6 publications found

Genes affected

STRA6 (HGNC:30650): (signaling receptor and transporter of retinol STRA6) The protein encoded by this gene is a membrane protein involved in the metabolism of retinol. The encoded protein acts as a receptor for retinol/retinol binding protein complexes. This protein removes the retinol from the complex and transports it across the cell membrane. Defects in this gene are a cause of syndromic microphthalmia type 9 (MCOPS9). Several transcript variants encoding a few different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

STRA6 Gene-Disease associations (from GenCC):

• Matthew-Wood syndrome

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• microphthalmia, isolated, with coloboma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006873369).
• BP6: Variant 15-74180181-C-T is Benign according to our data. Variant chr15-74180181-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 317096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00791 (1204/152262) while in subpopulation NFE AF = 0.012 (817/67998). AF 95% confidence interval is 0.0113. There are 8 homozygotes in GnomAd4. There are 605 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STRA6	NM_022369.4	c.1903G>A	p.Gly635Ser	missense_variant	Exon 19 of 19	ENST00000395105.9	NP_071764.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STRA6	ENST00000395105.9	c.1903G>A	p.Gly635Ser	missense_variant	Exon 19 of 19	1	NM_022369.4	ENSP00000378537.4

Frequencies

GnomAD3 genomes AF: 0.00791 AC: 1203 AN: 152144 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00215

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00785

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00456

Gnomad FIN AF: 0.0120

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.0120

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.00756 AC: 1897 AN: 250802 AF XY: 0.00795

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00408

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00935

Gnomad NFE exome AF: 0.0117

Gnomad OTH exome AF: 0.00540

GnomAD4 exome AF: 0.0109 AC: 15974 AN: 1461700 Hom.: 106 Cov.: 31 AF XY: 0.0108 AC XY: 7876 AN XY: 727174

African (AFR) AF: 0.00221 AC: 74 AN: 33480

American (AMR) AF: 0.00420 AC: 188 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00195 AC: 51 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00470 AC: 405 AN: 86240

European-Finnish (FIN) AF: 0.00768 AC: 409 AN: 53284

Middle Eastern (MID) AF: 0.0113 AC: 65 AN: 5768

European-Non Finnish (NFE) AF: 0.0128 AC: 14196 AN: 1111978

Other (OTH) AF: 0.00969 AC: 585 AN: 60396

GnomAD4 genome AF: 0.00791 AC: 1204 AN: 152262 Hom.: 8 Cov.: 33 AF XY: 0.00813 AC XY: 605 AN XY: 74452

African (AFR) AF: 0.00217 AC: 90 AN: 41558

American (AMR) AF: 0.00784 AC: 120 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00456 AC: 22 AN: 4822

European-Finnish (FIN) AF: 0.0120 AC: 127 AN: 10618

Middle Eastern (MID) AF: 0.0205 AC: 6 AN: 292

European-Non Finnish (NFE) AF: 0.0120 AC: 817 AN: 67998

Other (OTH) AF: 0.00758 AC: 16 AN: 2110

Alfa AF: 0.0103 Hom.: 33

Bravo AF: 0.00727

TwinsUK AF: 0.0119 AC: 44

ALSPAC AF: 0.0138 AC: 53

ESP6500AA AF: 0.00273 AC: 12

ESP6500EA AF: 0.0114 AC: 98

ExAC AF: 0.00736 AC: 894

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0136

EpiControl AF: 0.0118

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

STRA6: BP4, BS1, BS2 -

May 06, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Matthew-Wood syndrome Benign:2

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Inborn genetic diseases Benign:1

Aug 09, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	0.057
DANN	Benign	0.86
DEOGEN2	Benign	0.084	T;.;T;T;.;T;.;.;.
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0063	N
LIST_S2	Benign	0.52	.;T;.;.;T;T;T;T;T
MetaRNN	Benign	0.0069	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.42	N;.;N;N;.;N;.;.;.
PhyloP100		-0.68
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.84	N;N;N;.;.;.;N;.;.
REVEL	Benign	0.25
Sift	Benign	0.52	T;T;T;.;.;.;T;.;.
Sift4G	Benign	0.68	T;T;T;T;T;T;T;T;T
Polyphen		0.093	B;B;B;B;.;B;.;B;.
Vest4		0.11
MVP		0.19
MPC		0.094
ClinPred		0.00070	T
GERP RS		-4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.016
gMVP		0.21
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs145614612; hg19: chr15-74472522; COSMIC: COSV99997071; COSMIC: COSV99997071;