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.

• 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:4
• 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	Protein	UniProt
SLC1A4	NM_003038.5	c.1195G>A	p.Val399Ile	missense_variant	6/8	ENST00000234256.4	NP_003029.2
SLC1A4	NM_001348406.2	c.535G>A	p.Val179Ile	missense_variant	6/8		NP_001335335.1
SLC1A4	NM_001348407.2	c.535G>A	p.Val179Ile	missense_variant	6/8		NP_001335336.1
SLC1A4	NM_001193493.2	c.301G>A	p.Val101Ile	missense_variant	5/7		NP_001180422.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC1A4	ENST00000234256.4	c.1195G>A	p.Val399Ile	missense_variant	6/8	1	NM_003038.5	ENSP00000234256	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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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
DEOGEN2	Benign	0.17	.;T
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
MutationAssessor	Benign	0.045	.;N
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;