2-64989645-T-C

Position:

• chr2-64989645-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_003038.5(SLC1A4):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000731 in 1,367,286 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: SLC1A4 NM_003038.5 start_lost
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.95

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 Pathogenic. Variant got 11 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-64989645-T-C is Pathogenic according to our data. Variant chr2-64989645-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 2499988.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC1A4	NM_003038.5	c.2T>C	p.Met1?	start_lost	1/8	ENST00000234256.4
SLC1A4	NM_001193493.2	c.-134+1025T>C		intron_variant
SLC1A4	NM_001348406.2	c.-134+1025T>C		intron_variant
SLC1A4	NM_001348407.2	c.-134+1091T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC1A4	ENST00000234256.4	c.2T>C	p.Met1?	start_lost	1/8	1	NM_003038.5	P1
LINC02245	ENST00000653778.1	n.513+58309A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.31e-7 AC: 1 AN: 1367286 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 679932

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000133

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000836 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Pathogenic, no assertion criteria provided

clinical testing

Payam Genetics Center, General Welfare Department of North Khorasan Province

Mar 01, 2023

The SLC1A4 c.2T>C(p.M1T) results is a missense mutation and results is loss of start codon, predicted lead to disease. This variant is not present in population databases (ExAC no frequency) and was not found in 1000G, Genom AD exome, genome and Iranom. This variant has not been reported in the literature in individuals affected with SLC1A4-related conditions. We detected two brothers with similar clinical symptoms witch one of them died at 7 years old and one of them have been analyzed and detected homozygous c.2T>C variation at this SLC1A4 gene, the parents are consanguineous and both are carrier for this mutation. We classified this variant as Pathogenic according to our clinical evidence from this family. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.26	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.22
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.65	P
Vest4		0.82
MutPred		0.99		Gain of glycosylation at M1 (P = 0.0247);
MVP		0.74
ClinPred		0.99	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.69

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: rs747616493; hg19: chr2-65216779;