NM_014619.5:c.386T>C

Variant names:

• chr11-120819795-T-C
• rs1008330546
• NM_014619.5:c.386T>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014619.5(GRIK4):​c.386T>C​(p.Phe129Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRIK4 NM_014619.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.63

Genes affected

GRIK4 (HGNC:4582): (glutamate ionotropic receptor kainate type subunit 4) This gene encodes a protein that belongs to the glutamate-gated ionic channel family. Glutamate functions as the major excitatory neurotransmitter in the central nervous system through activation of ligand-gated ion channels and G protein-coupled membrane receptors. The protein encoded by this gene forms functional heteromeric kainate-preferring ionic channels with the subunits encoded by related gene family members. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30054128).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIK4	NM_014619.5	c.386T>C	p.Phe129Ser	missense_variant	Exon 6 of 21	ENST00000527524.8	NP_055434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIK4	ENST00000527524.8	c.386T>C	p.Phe129Ser	missense_variant	Exon 6 of 21	2	NM_014619.5	ENSP00000435648.2
GRIK4	ENST00000438375.2	c.386T>C	p.Phe129Ser	missense_variant	Exon 5 of 20	1		ENSP00000404063.2
GRIK4	ENST00000533291.5	n.784T>C		non_coding_transcript_exon_variant	Exon 6 of 18	1
GRIK4	ENST00000638419.1	c.386T>C	p.Phe129Ser	missense_variant	Exon 6 of 21	5		ENSP00000492086.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.386T>C (p.F129S) alteration is located in exon 4 (coding exon 4) of the GRIK4 gene. This alteration results from a T to C substitution at nucleotide position 386, causing the phenylalanine (F) at amino acid position 129 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;T;T
Eigen	Benign	0.087
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	.;.;T
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.30	T;T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.6	L;L;L
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.78	N;.;N
REVEL	Uncertain	0.38
Sift	Benign	0.40	T;.;T
Sift4G	Benign	0.40	T;.;T
Polyphen		0.40	B;B;B
Vest4		0.45
MutPred		0.42		Gain of disorder (P = 0.0242);Gain of disorder (P = 0.0242);Gain of disorder (P = 0.0242);
MVP		0.73
MPC		0.99
ClinPred		0.85	D
GERP RS		4.3
Varity_R		0.21
gMVP		0.70

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: rs1008330546; hg19: chr11-120690504;