rs201278558

Positions:

chr2-65010729-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PM2PP3PP5_Very_StrongBP4

The NM_003038.5(SLC1A4):c.766G>A(p.Glu256Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,613,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

SLC1A4
NM_003038.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 10.0

Variant links:

Genes affected

SLC1A4 (HGNC:10942): (solute carrier family 1 member 4) The protein encoded by this gene is a sodium-dependent neutral amino acid transporter for alanine, serine, cysteine, and threonine. Defects in this gene have been associated with developmental delay, microcephaly, and intellectual disability. [provided by RefSeq, Jan 2017]

SLC1A4 links:

SLC1A4 (HGNC:):

SLC1A4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Multiple lines of computational evidence support a deleterious effect 7: BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

PP5

Variant 2-65010729-G-A is Pathogenic according to our data. Variant chr2-65010729-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 265259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.2571743). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SLC1A4	NM_003038.5 linkuse as main transcript	c.766G>A	p.Glu256Lys	missense_variant	4/8	ENST00000234256.4	NP_003029.2
SLC1A4	NM_001348406.2 linkuse as main transcript	c.106G>A	p.Glu36Lys	missense_variant	4/8		NP_001335335.1
SLC1A4	NM_001348407.2 linkuse as main transcript	c.106G>A	p.Glu36Lys	missense_variant	4/8		NP_001335336.1
SLC1A4	NM_001193493.2 linkuse as main transcript	c.106G>A	p.Glu36Lys	missense_variant	4/7		NP_001180422.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC1A4	ENST00000234256.4 linkuse as main transcript	c.766G>A	p.Glu256Lys	missense_variant	4/8	1	NM_003038.5	ENSP00000234256.3		P43007-1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000235

AC:

AN:

251122

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

135698

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00467

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000125

AC:

182

AN:

1461686

Hom.:

Cov.:

AF XY:

0.000131

AC XY:

AN XY:

727142

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00482

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.000414

GnomAD4 genome

AF:

0.000105

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00375

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000510

Hom.:

Bravo

AF:

0.000128

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000173

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Spastic tetraplegia-thin corpus callosum-progressive postnatal microcephaly syndrome

Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Pediatric Genetics Clinic, Sheba Medical Center	May 13, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	May 29, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Nov 10, 2020	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Jun 08, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 15, 2020	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 03, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 256 of the SLC1A4 protein (p.Glu256Lys). This variant is present in population databases (rs201278558, gnomAD 0.5%). This missense change has been observed in individual(s) with spastic tetraplegia, thin corpus callosum, and progressive microcephaly (PMID: 25930971, 26041762, 26138499). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 265259). 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 SLC1A4 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SLC1A4 function (PMID: 26041762). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25930971, 26138499, 25256405, 27193218, 29652076, 26041762) -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 19, 2024

The c.766G>A (p.E256K) alteration is located in coding exon 4 of the SLC1A4 gene. This alteration results from a G to A substitution at nucleotide position 766, causing the glutamic acid (E) at amino acid position 256 to be replaced by a lysine (K). Based on data from gnomAD, the A allele has an overall frequency of 0.022% (62/282524) total alleles studied. The highest observed frequency was 0.473% (49/10356) of Ashkenazi Jewish alleles. This is a known founder variant in the Ashkenazi Jewish population. This variant has been identified in the homozygous state and/or in conjunction with other SLC1A4 variant(s) in individual(s) with features consistent with SLC1A4-related spastic tetraplegia, thin corpus callosum, and progressive microcephaly and segregated with disease in at least one family (Damseh, 2015; Srour, 2015). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.54

.;D

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.26

T;T

MetaSVM

Uncertain

-0.15

MutationAssessor

Pathogenic

3.0

.;M

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-2.5

D;D

REVEL

Uncertain

0.49

Sift

Uncertain

0.0050

D;D

Sift4G

Benign

0.23

T;T

Polyphen

0.99

.;D

Vest4

0.89

MVP

0.88

MPC

0.79

ClinPred

0.80

GERP RS

6.0

Varity_R

0.69

gMVP

0.90

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

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