2-65020916-C-T

Position:

chr2-65020916-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_003038.5(SLC1A4):c.1369C>T(p.Arg457Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000248 in 1,611,924 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

SLC1A4
NM_003038.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 5.95

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:

LINC02245 (HGNC:53134): (long intergenic non-protein coding RNA 2245)

LINC02245 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.801

PP5

Variant 2-65020916-C-T is Pathogenic according to our data. Variant chr2-65020916-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-65020916-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SLC1A4	NM_003038.5 linkuse as main transcript	c.1369C>T	p.Arg457Trp	missense_variant	8/8	ENST00000234256.4	NP_003029.2
SLC1A4	NM_001348406.2 linkuse as main transcript	c.709C>T	p.Arg237Trp	missense_variant	8/8		NP_001335335.1
SLC1A4	NM_001348407.2 linkuse as main transcript	c.709C>T	p.Arg237Trp	missense_variant	8/8		NP_001335336.1
SLC1A4	NM_001193493.2 linkuse as main transcript	c.475C>T	p.Arg159Trp	missense_variant	7/7		NP_001180422.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC1A4	ENST00000234256.4 linkuse as main transcript	c.1369C>T	p.Arg457Trp	missense_variant	8/8	1	NM_003038.5	ENSP00000234256	P1	P43007-1
LINC02245	ENST00000653778.1 linkuse as main transcript	n.513+27038G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

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:

0.000123

AC:

AN:

251166

Hom.:

AF XY:

0.0000810

AC XY:

AN XY:

135722

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000781

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:

0.00

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.0000260

AC:

AN:

1459754

Hom.:

Cov.:

AF XY:

0.0000262

AC XY:

AN XY:

726322

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.000693

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:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

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

Bravo

AF:

0.0000264

ExAC

AF:

0.000157

AC:

ClinVar

Significance: Pathogenic/Likely 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:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 15, 2020	- -
Pathogenic, no assertion criteria provided	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	-	This variant was identified in an individual with developmental delay, microcephaly, corpus callosum agenesis, hypomyelination. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 16, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 03, 2023	Variant summary: SLC1A4 c.1369C>T (p.Arg457Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 251166 control chromosomes (gnomAD). c.1369C>T has been reported in the literature in the homozygous state in two unrelated individuals affected with Spastic Tetraplegia-Thin Corpus Callosum-Progressive Postnatal Microcephaly Syndrome (Damseh_2015, Eldomery_2017). These data indicate that the variant is likely to be associated with disease. A functional study found that although the variant protein is expressed at a similar level as the WT protein at the plasma membrane, it has no detectable transport activity (Damseh_2015). The following publications have been ascertained in the context of this evaluation (PMID: 26041762, 28327206). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=4)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 14, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 457 of the SLC1A4 protein (p.Arg457Trp). This variant is present in population databases (rs761533681, gnomAD 0.05%). This missense change has been observed in individuals with spastic tetraplegia, thin corpus callosum, and progressive microcephaly (PMID: 2837306, 26041762; Invitae). ClinVar contains an entry for this variant (Variation ID: 372158). 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 expected to disrupt SLC1A4 protein function. Experimental studies have shown that this missense change affects SLC1A4 function (PMID: 26041762). This variant disrupts the p.Arg457 amino acid residue in SLC1A4. Other variant(s) that disrupt this residue have been observed in individuals with SLC1A4-related conditions (PMID: 26041762, 34174466), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 10, 2024	Published functional studies demonstrate p.R457W impairs transporter activity (PMID: 26041762); 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: 31763347, 26041762, Stehantsev2021[article], 33310157, 34174466, 37194416, 28327206, 2837306) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	SLC1A4: PM2, PM3, PP3, PS4:Supporting -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 04, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.77

.;D

Eigen

Pathogenic

0.77

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.80

D;D

MetaSVM

Uncertain

0.30

MutationAssessor

Pathogenic

4.4

.;H

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-7.4

D;D

REVEL

Pathogenic

0.76

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

.;D

Vest4

0.95

MutPred

0.69

.;Gain of sheet (P = 0.0085);

MVP

0.90

MPC

1.1

ClinPred

0.99

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.98

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