rs759458

Variant names:

• chr2-65018231-G-A
• rs759458
• NM_003038.5:c.1195G>A

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). 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:4
• Conservation: PhyloP100: 0.526
• Publications: 49 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003038.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC1A4	NM_003038.5	MANE Select	c.1195G>A	p.Val399Ile	missense	Exon 6 of 8	NP_003029.2
	SLC1A4	NM_001348406.2		c.535G>A	p.Val179Ile	missense	Exon 6 of 8	NP_001335335.1
	SLC1A4	NM_001348407.2		c.535G>A	p.Val179Ile	missense	Exon 6 of 8	NP_001335336.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC1A4	ENST00000234256.4	TSL:1 MANE Select	c.1195G>A	p.Val399Ile	missense	Exon 6 of 8	ENSP00000234256.3	P43007-1
	SLC1A4	ENST00000906286.1		c.1195G>A	p.Val399Ile	missense	Exon 7 of 9	ENSP00000576345.1
	SLC1A4	ENST00000906287.1		c.1132G>A	p.Val378Ile	missense	Exon 5 of 7	ENSP00000576346.1

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

GnomAD2 exomes AF: 0.235 AC: 58965 AN: 251332 AF XY: 0.247

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 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

African (AFR) AF: 0.167 AC: 5604 AN: 33478

American (AMR) AF: 0.149 AC: 6658 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 9013 AN: 26134

East Asian (EAS) AF: 0.131 AC: 5197 AN: 39698

South Asian (SAS) AF: 0.315 AC: 27157 AN: 86256

European-Finnish (FIN) AF: 0.230 AC: 12275 AN: 53420

Middle Eastern (MID) AF: 0.375 AC: 2162 AN: 5768

European-Non Finnish (NFE) AF: 0.255 AC: 283147 AN: 1111880

Other (OTH) AF: 0.264 AC: 15961 AN: 60386

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

African (AFR) AF: 0.164 AC: 6808 AN: 41490

American (AMR) AF: 0.193 AC: 2941 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.335 AC: 1163 AN: 3472

East Asian (EAS) AF: 0.130 AC: 672 AN: 5184

South Asian (SAS) AF: 0.302 AC: 1450 AN: 4806

European-Finnish (FIN) AF: 0.235 AC: 2481 AN: 10552

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.254 AC: 17278 AN: 67990

Other (OTH) AF: 0.248 AC: 523 AN: 2108

Alfa AF: 0.250 Hom.: 16240

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Spastic tetraplegia-thin corpus callosum-progressive postnatal microcephaly syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.045	N
PhyloP100		0.53
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.045
Sift	Benign	0.39	T
Sift4G	Benign	0.42	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
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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