Genetic Variant STRA6:p.Arg638Pro (chr15-74180171-C-G) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_022369.4(STRA6):c.1913G>C(p.Arg638Pro) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R638H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

STRA6
NM_022369.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.47

Publications

2 publications found

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 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

STRA6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.958

PP5

Variant 15-74180171-C-G is Pathogenic according to our data. Variant chr15-74180171-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 221967.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
STRA6	NM_022369.4	MANE Select	c.1913G>C	p.Arg638Pro	missense	Exon 19 of 19	NP_071764.3
STRA6	NM_001199042.2		c.2030G>C	p.Arg677Pro	missense	Exon 19 of 19	NP_001185971.1
STRA6	NM_001199040.2		c.2024G>C	p.Arg675Pro	missense	Exon 19 of 19	NP_001185969.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
STRA6	ENST00000395105.9	TSL:1 MANE Select	c.1913G>C	p.Arg638Pro	missense	Exon 19 of 19	ENSP00000378537.4
STRA6	ENST00000563965.5	TSL:1	c.2030G>C	p.Arg677Pro	missense	Exon 19 of 19	ENSP00000456609.1
STRA6	ENST00000423167.6	TSL:1	c.1886G>C	p.Arg629Pro	missense	Exon 19 of 19	ENSP00000413012.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Anophthalmia-microphthalmia syndrome

Pathogenic:1

Jan 01, 2013

Paul Sabatier University EA-4555, Paul Sabatier University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

rare variant, predicted damaging in silico (Polyphen-2, SIFT), compound heterozygosity

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.61

MutationAssessor

Uncertain

2.8

PhyloP100

3.5

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-5.0

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0030

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.96

MVP

0.91

MPC

0.59

ClinPred

0.99

GERP RS

4.5

Varity_R

0.93

gMVP

0.86

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over