chr16-84042063-A-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_001080442.3(SLC38A8):c.95T>G(p.Ile32Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

SLC38A8
NM_001080442.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 8.70

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 links:

ENSG00000285792 (HGNC:):

ENSG00000285792 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a transmembrane_region Helical (size 20) in uniprot entity S38A8_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001080442.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.908

PP5

Variant 16-84042063-A-C is Pathogenic according to our data. Variant chr16-84042063-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 125442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-84042063-A-C is described in Lovd as [Likely_pathogenic]. Variant chr16-84042063-A-C is described in Lovd as [Likely_pathogenic]. Variant chr16-84042063-A-C is described in Lovd as [Likely_pathogenic]. Variant chr16-84042063-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC38A8	NM_001080442.3 link	c.95T>G	p.Ile32Ser	missense_variant	Exon 2 of 11	ENST00000299709.8	NP_001073911.1	A6NNN8
SLC38A8	XM_017022946.1 link	c.95T>G	p.Ile32Ser	missense_variant	Exon 3 of 12		XP_016878435.1	A6NNN8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC38A8	ENST00000299709.8 link	c.95T>G	p.Ile32Ser	missense_variant	Exon 2 of 11	5	NM_001080442.3	ENSP00000299709.3	A6NNN8
SLC38A8	ENST00000568178.1 link	c.95T>G	p.Ile32Ser	missense_variant	Exon 2 of 7	5		ENSP00000457737.1	H3BUP5
ENSG00000285792	ENST00000647688.1 link	n.1274A>C		non_coding_transcript_exon_variant	Exon 1 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251200

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135770

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461744

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727178

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome

Pathogenic:2

Feb 10, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SLC38A8 c.95T>G (p.Ile32Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251200 control chromosomes. c.95T>G has been reported in the literature in multiple individuals affected with Foveal Hypoplasia, Optic Nerve Decussation Defect, Anterior Segment Dysgenesis Syndrome (example: Perez_2013). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 24045842). ClinVar contains an entry for this variant (Variation ID: 125442). Based on the evidence outlined above, the variant was classified as pathogenic. -

Sep 18, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Foveal hypoplasia

Pathogenic:1

Jun 23, 2019

Sharon lab, Hadassah-Hebrew University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided

Pathogenic:1

Nov 09, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 32 of the SLC38A8 protein (p.Ile32Ser). This variant is present in population databases (rs587777253, gnomAD 0.0009%). This missense change has been observed in individual(s) with foveal hypoplasia (PMID: 24045842, 32032626, 33594928). It is commonly reported in individuals of Indian Jewish ancestry (PMID: 24045842, 35029636). ClinVar contains an entry for this variant (Variation ID: 125442). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SLC38A8 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

T;.

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;D

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Benign

-1.2

MutationAssessor

Pathogenic

3.0

M;.

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-5.0

D;D

REVEL

Pathogenic

0.78

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.95

MutPred

0.67

Gain of disorder (P = 0.0034);Gain of disorder (P = 0.0034);

MVP

0.26

ClinPred

1.0

GERP RS

5.0

Varity_R

0.85

gMVP

0.72

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

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