2-164494433-G-T

Variant names:

• chr2-164494433-G-T
• rs747345020
• NM_004490.3:c.1474C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004490.3(GRB14):​c.1474C>A​(p.Pro492Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P492S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GRB14 NM_004490.3 missense, splice_region
• Scores: Splicing: ADA: 0.9487
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.02
• Publications: 0 publications found

Genes affected

GRB14 (HGNC:4565): (growth factor receptor bound protein 14) The product of this gene belongs to a small family of adapter proteins that are known to interact with a number of receptor tyrosine kinases and signaling molecules. This gene encodes a growth factor receptor-binding protein that interacts with insulin receptors and insulin-like growth-factor receptors. This protein likely has an inhibitory effect on receptor tyrosine kinase signaling and, in particular, on insulin receptor signaling. This gene may play a role in signaling pathways that regulate growth and metabolism. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRB14	NM_004490.3	c.1474C>A	p.Pro492Thr	missense_variant, splice_region_variant	Exon 13 of 14	ENST00000263915.8	NP_004481.2
GRB14	NM_001303422.2	c.1213C>A	p.Pro405Thr	missense_variant, splice_region_variant	Exon 12 of 13		NP_001290351.1
GRB14	XM_047444013.1	c.874C>A	p.Pro292Thr	missense_variant, splice_region_variant	Exon 12 of 13		XP_047299969.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRB14	ENST00000263915.8	c.1474C>A	p.Pro492Thr	missense_variant, splice_region_variant	Exon 13 of 14	1	NM_004490.3	ENSP00000263915.3
GRB14	ENST00000696453.2	c.1213C>A	p.Pro405Thr	missense_variant, splice_region_variant	Exon 12 of 13			ENSP00000512640.1
GRB14	ENST00000488342.5	n.1610C>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 13 of 14	5
GRB14	ENST00000497306.1	n.46-1251C>A		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.35e-7 AC: 1 AN: 1360318 Hom.: 0 Cov.: 23 AF XY: 0.00000146 AC XY: 1 AN XY: 682686

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31494

American (AMR) AF: 0.00 AC: 0 AN: 44542

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25478

East Asian (EAS) AF: 0.00 AC: 0 AN: 39128

South Asian (SAS) AF: 0.00 AC: 0 AN: 84118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5562

European-Non Finnish (NFE) AF: 9.81e-7 AC: 1 AN: 1019828

Other (OTH) AF: 0.00 AC: 0 AN: 56816

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Benign	1.1	L
PhyloP100		8.0
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.99	D
Vest4		0.53
MutPred		0.45		Loss of catalytic residue at P492 (P = 0.0407);
MVP		0.96
MPC		0.14
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.91
gMVP		0.52
Mutation Taster		=11/89	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.95
dbscSNV1_RF	Pathogenic	0.81
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: rs747345020; hg19: chr2-165350943;