dbSNP rs587777254: SLC38A8:p.Val236Ala (chr16-84022873-A-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PM5

The NM_001080442.3(SLC38A8):c.707T>C(p.Val236Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,938 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V236D) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SLC38A8
NM_001080442.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.87

Publications

0 publications found

Variant links:

Genes affected

SLC38A8 (HGNC:32434): (solute carrier family 38 member 8) This gene encodes a putative sodium-dependent amino-acid/proton antiporter. The protein has eleven transmembrane domains, an extracellular N-terminus and an intracellular C-terminal tail. The protein is a member of the SLC38 sodium-coupled neutral amino acid transporter family of proteins. Mutations in this gene result in foveal hypoplasia with or without optic nerve misrouting and/or anterior segment dysgenesis. [provided by RefSeq, May 2014]

SLC38A8 Gene-Disease associations (from GenCC):

foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics

SLC38A8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001080442.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-84022873-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 125443.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC38A8	NM_001080442.3 link	c.707T>C	p.Val236Ala	missense_variant	Exon 7 of 11	ENST00000299709.8	NP_001073911.1	A6NNN8
SLC38A8	XM_017022946.1 link	c.707T>C	p.Val236Ala	missense_variant	Exon 8 of 12		XP_016878435.1	A6NNN8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC38A8	ENST00000299709.8 link	c.707T>C	p.Val236Ala	missense_variant	Exon 7 of 11	5	NM_001080442.3	ENSP00000299709.3		A6NNN8
SLC38A8	ENST00000568178.1 link	c.707T>C	p.Val236Ala	missense_variant	Exon 7 of 7	5		ENSP00000457737.1		H3BUP5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1453938

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723258

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32980

American (AMR)

AF:

0.00

AC:

AN:

42872

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25592

East Asian (EAS)

AF:

0.00

AC:

AN:

39320

South Asian (SAS)

AF:

0.0000118

AC:

AN:

85044

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53244

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109078

Other (OTH)

AF:

0.00

AC:

AN:

60108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Benign

-0.065

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.17

T;.

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.043

MetaRNN

Uncertain

0.68

D;D

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

M;.

PhyloP100

8.9

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-3.6

D;D

REVEL

Uncertain

0.33

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

0.99

D;.

Vest4

0.60

MutPred

0.68

Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);

MVP

0.12

ClinPred

0.97

GERP RS

5.4

Varity_R

0.56

gMVP

0.71

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over