2-64989683-G-A

Position:

• chr2-64989683-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003038.5(SLC1A4):​c.40G>A​(p.Ala14Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00888 in 1,541,462 control chromosomes in the GnomAD database, including 76 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A14A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0064 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0092 (69 hom.)
• Consequence: SLC1A4 NM_003038.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0310

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=0.0034198463).
• BP6: Variant 2-64989683-G-A is Benign according to our data. Variant chr2-64989683-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 444499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00635 (967/152226) while in subpopulation AMR AF= 0.0117 (179/15306). AF 95% confidence interval is 0.0103. There are 7 homozygotes in gnomad4. There are 455 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC1A4	NM_003038.5	c.40G>A	p.Ala14Thr	missense_variant	1/8	ENST00000234256.4
SLC1A4	NM_001193493.2	c.-134+1063G>A		intron_variant
SLC1A4	NM_001348406.2	c.-134+1063G>A		intron_variant
SLC1A4	NM_001348407.2	c.-134+1129G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC1A4	ENST00000234256.4	c.40G>A	p.Ala14Thr	missense_variant	1/8	1	NM_003038.5	P1
LINC02245	ENST00000653778.1	n.513+58271C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00636 AC: 968 AN: 152114 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.0287

Gnomad NFE AF: 0.00944

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00560 AC: 976 AN: 174216 Hom.: 4 AF XY: 0.00595 AC XY: 588 AN XY: 98790

Gnomad AFR exome AF: 0.00209

Gnomad AMR exome AF: 0.00392

Gnomad ASJ exome AF: 0.00662

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00204

Gnomad FIN exome AF: 0.000771

Gnomad NFE exome AF: 0.00905

Gnomad OTH exome AF: 0.00631

GnomAD4 exome AF: 0.00915 AC: 12715 AN: 1389236 Hom.: 69 Cov.: 30 AF XY: 0.00903 AC XY: 6238 AN XY: 690996

Gnomad4 AFR exome AF: 0.00142

Gnomad4 AMR exome AF: 0.00380

Gnomad4 ASJ exome AF: 0.00608

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00266

Gnomad4 FIN exome AF: 0.00142

Gnomad4 NFE exome AF: 0.0108

Gnomad4 OTH exome AF: 0.00743

GnomAD4 genome AF: 0.00635 AC: 967 AN: 152226 Hom.: 7 Cov.: 33 AF XY: 0.00611 AC XY: 455 AN XY: 74428

Gnomad4 AFR AF: 0.00173

Gnomad4 AMR AF: 0.0117

Gnomad4 ASJ AF: 0.00836

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00248

Gnomad4 FIN AF: 0.000848

Gnomad4 NFE AF: 0.00944

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00858 Hom.: 8

Bravo AF: 0.00642

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00242 AC: 10

ESP6500EA AF: 0.00800 AC: 65

ExAC AF: 0.00527 AC: 624

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	LINC02245: BS2; SLC1A4: PP2, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.041
Sift	Benign	0.38	T
Sift4G	Benign	0.47	T
Polyphen		0.0030	B
Vest4		0.073
MVP		0.42
MPC		1.3
ClinPred		0.012	T
GERP RS		0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.030
gMVP		0.31

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: rs149636167; hg19: chr2-65216817;