rs145614612

chr15-74180181-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 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. 15/20 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:5
• Conservation: PhyloP100: -0.683

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_022369.4
• 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 [Likely_benign]. Clinvar id is 317096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-74180181-C-T is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STRA6	NM_022369.4	c.1903G>A	p.Gly635Ser	missense_variant	19/19	ENST00000395105.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STRA6	ENST00000395105.9	c.1903G>A	p.Gly635Ser	missense_variant	19/19	1	NM_022369.4	P1

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

GnomAD3 exomes AF: 0.00756 AC: 1897 AN: 250802 Hom.: 10 AF XY: 0.00795 AC XY: 1078 AN XY: 135608

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 SAS exome AF: 0.00503

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

Gnomad4 AFR exome AF: 0.00221

Gnomad4 AMR exome AF: 0.00420

Gnomad4 ASJ exome AF: 0.00195

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00470

Gnomad4 FIN exome AF: 0.00768

Gnomad4 NFE exome AF: 0.0128

Gnomad4 OTH exome AF: 0.00969

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

Gnomad4 AFR AF: 0.00217

Gnomad4 AMR AF: 0.00784

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00456

Gnomad4 FIN AF: 0.0120

Gnomad4 NFE AF: 0.0120

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.0105 Hom.: 17

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Matthew-Wood syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2021	See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	STRA6: BP4, BS1, BS2 -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2021

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
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;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
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

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