rs118203962

Variant names:

• chr15-74189244-T-G
• rs118203962
• NM_022369.4:c.961A>C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_022369.4(STRA6):​c.961A>C​(p.Thr321Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000729 in 1,607,106 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00076 (2 hom.)
• Consequence: STRA6 NM_022369.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 1.11

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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000407 (62/152244) while in subpopulation NFE AF= 0.000691 (47/67994). AF 95% confidence interval is 0.000534. There are 0 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STRA6	NM_022369.4	c.961A>C	p.Thr321Pro	missense_variant	Exon 12 of 19	ENST00000395105.9	NP_071764.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STRA6	ENST00000395105.9	c.961A>C	p.Thr321Pro	missense_variant	Exon 12 of 19	1	NM_022369.4	ENSP00000378537.4

Frequencies

GnomAD3 genomes AF: 0.000408 AC: 62 AN: 152126 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000538 AC: 126 AN: 234268 Hom.: 0 AF XY: 0.000593 AC XY: 75 AN XY: 126470

Gnomad AFR exome AF: 0.000137

Gnomad AMR exome AF: 0.0000912

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000663

Gnomad FIN exome AF: 0.000450

Gnomad NFE exome AF: 0.000864

Gnomad OTH exome AF: 0.000348

GnomAD4 exome AF: 0.000763 AC: 1110 AN: 1454862 Hom.: 2 Cov.: 32 AF XY: 0.000790 AC XY: 571 AN XY: 722954

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000688

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000637

Gnomad4 FIN exome AF: 0.000398

Gnomad4 NFE exome AF: 0.000899

Gnomad4 OTH exome AF: 0.000565

GnomAD4 genome AF: 0.000407 AC: 62 AN: 152244 Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74440

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000678 Hom.: 0

Bravo AF: 0.000457

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000437 AC: 53

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Matthew-Wood syndrome Pathogenic:1

Mar 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

STRA6-related disorder Uncertain:1

Nov 14, 2022

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The STRA6 c.961A>C variant is predicted to result in the amino acid substitution p.Thr321Pro. This variant was reported in homozygous state, along with another homozygous variant in STRA6 [c.269C>T (p.Pro90Leu)], in an individual with bilateral anophthalmia, hypoplastic lung, congenial diaphragmatic hernia, diaphragmatic eventration, persistent ductus arteriosus, hypoplastic kidney, bicornuate uterus who passed away at one day of life (MWS6-BK, Pasutto et al. 2007. PubMed ID: 17273977). Of note, consanguinity was noted for that patient, however, no other family members were available to additional genetic analyses. Additional protein structure analyses were performed via computational analyses on both variants present in that patient and it was determined that the p.Thr321Pro and p.Pro90Leu variants would both impact protein structure of STRA6 (Pasutto et al. 2007. PubMed ID: 17273977). This variant is reported in 0.081% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-74481585-T-G). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;.;D;D;.;D;.;.;.
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.62	.;T;.;.;T;T;T;T;T
M_CAP	Benign	0.074	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.7	M;.;M;M;.;M;.;.;.
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.9	D;D;D;.;.;.;D;.;.
REVEL	Pathogenic	0.72
Sift	Uncertain	0.010	D;D;D;.;.;.;D;.;.
Sift4G	Uncertain	0.020	D;D;D;D;D;D;D;D;D
Polyphen		0.98	D;D;D;D;.;D;.;D;.
Vest4		0.80
MVP		0.86
MPC		0.51
ClinPred		0.089	T
GERP RS		4.0
Varity_R		0.55
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs118203962; hg19: chr15-74481585;