rs759458

Positions:

• chr2-65018231-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003038.5(SLC1A4):​c.1195G>A​(p.Val399Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 1,613,822 control chromosomes in the GnomAD database, including 51,425 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. V399V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.22 (3936 hom., cov: 32)
  • Exomes 𝑓: 0.25 (47489 hom.)
• Consequence: SLC1A4 NM_003038.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.526

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]

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

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019662976).
• BP6: Variant 2-65018231-G-A is Benign according to our data. Variant chr2-65018231-G-A is described in ClinVar as [Benign]. Clinvar id is 1167921.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.289 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC1A4	NM_003038.5	c.1195G>A	p.Val399Ile	missense_variant	6/8	ENST00000234256.4
SLC1A4	NM_001348406.2	c.535G>A	p.Val179Ile	missense_variant	6/8
SLC1A4	NM_001348407.2	c.535G>A	p.Val179Ile	missense_variant	6/8
SLC1A4	NM_001193493.2	c.301G>A	p.Val101Ile	missense_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC1A4	ENST00000234256.4	c.1195G>A	p.Val399Ile	missense_variant	6/8	1	NM_003038.5	P1
LINC02245	ENST00000653778.1	n.513+29723C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33569 AN: 151964 Hom.: 3938 Cov.: 32

Gnomad AFR AF: 0.164

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.335

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.302

Gnomad FIN AF: 0.235

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.254

Gnomad OTH AF: 0.249

GnomAD3 exomes AF: 0.235 AC: 58965 AN: 251332 Hom.: 7494 AF XY: 0.247 AC XY: 33490 AN XY: 135820

Gnomad AFR exome AF: 0.164

Gnomad AMR exome AF: 0.143

Gnomad ASJ exome AF: 0.341

Gnomad EAS exome AF: 0.130

Gnomad SAS exome AF: 0.317

Gnomad FIN exome AF: 0.230

Gnomad NFE exome AF: 0.257

Gnomad OTH exome AF: 0.265

GnomAD4 exome AF: 0.251 AC: 367174 AN: 1461740 Hom.: 47489 Cov.: 34 AF XY: 0.254 AC XY: 184843 AN XY: 727170

Gnomad4 AFR exome AF: 0.167

Gnomad4 AMR exome AF: 0.149

Gnomad4 ASJ exome AF: 0.345

Gnomad4 EAS exome AF: 0.131

Gnomad4 SAS exome AF: 0.315

Gnomad4 FIN exome AF: 0.230

Gnomad4 NFE exome AF: 0.255

Gnomad4 OTH exome AF: 0.264

GnomAD4 genome AF: 0.221 AC: 33573 AN: 152082 Hom.: 3936 Cov.: 32 AF XY: 0.218 AC XY: 16171 AN XY: 74316

Gnomad4 AFR AF: 0.164

Gnomad4 AMR AF: 0.193

Gnomad4 ASJ AF: 0.335

Gnomad4 EAS AF: 0.130

Gnomad4 SAS AF: 0.302

Gnomad4 FIN AF: 0.235

Gnomad4 NFE AF: 0.254

Gnomad4 OTH AF: 0.248

Alfa AF: 0.255 Hom.: 12770

Bravo AF: 0.213

TwinsUK AF: 0.244 AC: 905

ALSPAC AF: 0.256 AC: 986

ESP6500AA AF: 0.175 AC: 772

ESP6500EA AF: 0.262 AC: 2257

ExAC AF: 0.240 AC: 29147

Asia WGS AF: 0.254 AC: 883 AN: 3478

EpiCase AF: 0.274

EpiControl AF: 0.272

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

Spastic tetraplegia-thin corpus callosum-progressive postnatal microcephaly syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	4.7
DANN	Benign	0.90
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.48	T;T
MetaRNN	Benign	0.0020	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.23	N;N
REVEL	Benign	0.045
Sift	Benign	0.39	T;T
Sift4G	Benign	0.42	T;T
Polyphen		0.0020	.;B
Vest4		0.037
MPC		0.26
ClinPred		0.0011	T
GERP RS		0.22
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.049
gMVP		0.56

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

Other links and lift over

dbSNP: rs759458; hg19: chr2-65245365; COSMIC: COSV52234002; COSMIC: COSV52234002;