15-74181398-C-G

Variant names:

• chr15-74181398-C-G
• rs736118
• NM_022369.4:c.1581G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022369.4(STRA6):​c.1581G>C​(p.Met527Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: STRA6 NM_022369.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.382
• Publications: 44 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09874633).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STRA6	NM_022369.4	c.1581G>C	p.Met527Ile	missense_variant	Exon 17 of 19	ENST00000395105.9	NP_071764.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STRA6	ENST00000395105.9	c.1581G>C	p.Met527Ile	missense_variant	Exon 17 of 19	1	NM_022369.4	ENSP00000378537.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 3697

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	4.1
DANN	Benign	0.96
DEOGEN2	Benign	0.090	T;.;T;T;.;T;.;.;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.49
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.67	.;T;.;.;T;T;T;T;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.099	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.1	L;.;L;L;.;L;.;.;.
PhyloP100		0.38
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.20	N;N;N;N;.;.;N;.;.
REVEL	Benign	0.15
Sift	Benign	0.85	T;T;T;T;.;.;T;.;.
Sift4G	Benign	0.23	T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;.;B;.;B;.
Vest4		0.049
MutPred		0.14		Gain of catalytic residue at M527 (P = 0.109);.;Gain of catalytic residue at M527 (P = 0.109);Gain of catalytic residue at M527 (P = 0.109);.;Gain of catalytic residue at M527 (P = 0.109);.;.;.;
MVP		0.41
MPC		0.10
ClinPred		0.23	T
GERP RS		3.8
Varity_R		0.044
gMVP		0.20
Mutation Taster		=99/1	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: rs736118; hg19: chr15-74473739;