rs118203962

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

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 (★). Synonymous variant affecting the same amino acid position (i.e. T321T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00076 ( 2 hom. )

Consequence

STRA6
NM_022369.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 1.11

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STRA6	NM_022369.4 linkuse as main transcript	c.961A>C	p.Thr321Pro	missense_variant	12/19	ENST00000395105.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STRA6	ENST00000395105.9 linkuse as main transcript	c.961A>C	p.Thr321Pro	missense_variant	12/19	1	NM_022369.4	P1	Q9BX79-1

Frequencies

GnomAD3 genomes

AF:

0.000408

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.000593

AC XY:

AN XY:

126470

show subpopulations

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.:

Cov.:

AF XY:

0.000790

AC XY:

571

AN XY:

722954

show subpopulations

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:

AN:

152244

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74440

show subpopulations

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.:

Bravo

AF:

0.000457

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000437

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Matthew-Wood syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2007

- -

STRA6-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 14, 2022

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

BayesDel_noAF

Pathogenic

0.23

Cadd

Uncertain

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

M_CAP

Benign

0.074

MetaRNN

Uncertain

0.60

D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.27

MutationAssessor

Uncertain

2.7

M;.;M;M;.;M;.;.;.

MutationTaster

Benign

0.88

A;A;A;A;A;A;A;A

PrimateAI

Benign

0.29

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over