rs118203962

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -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 (★★). 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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:3
• Conservation: PhyloP100: 1.11
• Publications: 10 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: Likely_benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022369.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STRA6	NM_022369.4	MANE Select	c.961A>C	p.Thr321Pro	missense	Exon 12 of 19	NP_071764.3
	STRA6	NM_001199042.2		c.1078A>C	p.Thr360Pro	missense	Exon 12 of 19	NP_001185971.1
	STRA6	NM_001199040.2		c.1072A>C	p.Thr358Pro	missense	Exon 12 of 19	NP_001185969.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STRA6	ENST00000395105.9	TSL:1 MANE Select	c.961A>C	p.Thr321Pro	missense	Exon 12 of 19	ENSP00000378537.4
	STRA6	ENST00000563965.5	TSL:1	c.1078A>C	p.Thr360Pro	missense	Exon 12 of 19	ENSP00000456609.1
	STRA6	ENST00000423167.6	TSL:1	c.934A>C	p.Thr312Pro	missense	Exon 12 of 19	ENSP00000413012.2

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

GnomAD2 exomes AF: 0.000538 AC: 126 AN: 234268 AF XY: 0.000593

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 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

African (AFR) AF: 0.0000299 AC: 1 AN: 33390

American (AMR) AF: 0.0000688 AC: 3 AN: 43592

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25890

East Asian (EAS) AF: 0.00 AC: 0 AN: 39498

South Asian (SAS) AF: 0.000637 AC: 54 AN: 84798

European-Finnish (FIN) AF: 0.000398 AC: 21 AN: 52726

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000899 AC: 997 AN: 1109050

Other (OTH) AF: 0.000565 AC: 34 AN: 60152

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

African (AFR) AF: 0.000241 AC: 10 AN: 41548

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000691 AC: 47 AN: 67994

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000663 Hom.: 1

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

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	1	-	Matthew-Wood syndrome (2)
-	1	-	not provided (1)
-	1	-	STRA6-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.074	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		1.1
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.020	D
Polyphen		0.98	D
Vest4		0.80
MVP		0.86
MPC		0.51
ClinPred		0.089	T
GERP RS		4.0
PromoterAI		-0.0018	Neutral
Varity_R		0.55
gMVP		0.81
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs118203962; hg19: chr15-74481585;