5-126465433-G-A

Variant names:

• chr5-126465433-G-A
• rs773306903
• NM_023927.4:c.91G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_023927.4(GRAMD2B):​c.91G>A​(p.Ala31Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRAMD2B NM_023927.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.49

Genes affected

GRAMD2B (HGNC:24911): (GRAM domain containing 2B) Enables identical protein binding activity. Located in cytoplasmic microtubule. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000250602 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09601614).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRAMD2B	NM_023927.4	c.91G>A	p.Ala31Thr	missense_variant	Exon 2 of 14	ENST00000285689.8	NP_076416.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRAMD2B	ENST00000285689.8	c.91G>A	p.Ala31Thr	missense_variant	Exon 2 of 14	1	NM_023927.4	ENSP00000285689.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.136G>A (p.A46T) alteration is located in exon 2 (coding exon 2) of the GRAMD3 gene. This alteration results from a G to A substitution at nucleotide position 136, causing the alanine (A) at amino acid position 46 to be replaced by a threonine (T). 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	0.081
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	.;T;T;T;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.85	D;T;D;D;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.096	T;T;T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.87	N;N;N;N;N
REVEL	Benign	0.049
Sift	Benign	0.23	T;T;T;T;T
Sift4G	Benign	0.34	T;T;T;T;T
Polyphen		0.0020	.;.;B;.;.
Vest4		0.26
MutPred		0.11		.;.;Gain of phosphorylation at A31 (P = 0.0168);Gain of phosphorylation at A31 (P = 0.0168);.;
MVP		0.36
MPC		0.20
ClinPred		0.87	D
GERP RS		2.9
Varity_R		0.051
gMVP		0.095

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: rs773306903; hg19: chr5-125801125;