chr22-39960155-G-T

Position:

• chr22-39960155-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004810.4(GRAP2):​c.271G>T​(p.Asp91Tyr) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRAP2 NM_004810.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.86

Genes affected

GRAP2 (HGNC:4563): (GRB2 related adaptor protein 2) This gene encodes a member of the GRB2/Sem5/Drk family. This member is an adaptor-like protein involved in leukocyte-specific protein-tyrosine kinase signaling. Like its related family member, GRB2-related adaptor protein (GRAP), this protein contains an SH2 domain flanked by two SH3 domains. This protein interacts with other proteins, such as GRB2-associated binding protein 1 (GAB1) and the SLP-76 leukocyte protein (LCP2), through its SH3 domains. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Apr 2014]

GRAP2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.849

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRAP2	NM_004810.4	c.271G>T	p.Asp91Tyr	missense_variant	4/8	ENST00000344138.9	NP_004801.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRAP2	ENST00000344138.9	c.271G>T	p.Asp91Tyr	missense_variant	4/8	1	NM_004810.4	ENSP00000339186.4
GRAP2	ENST00000407075.3	c.271G>T	p.Asp91Tyr	missense_variant	3/7	1		ENSP00000385607.3
GRAP2	ENST00000420971.5	c.271G>T	p.Asp91Tyr	missense_variant	4/4	2		ENSP00000396355.1
GRAP2	ENST00000478445.1	n.444G>T		non_coding_transcript_exon_variant	3/4	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 09, 2024

The c.271G>T (p.D91Y) alteration is located in exon 4 (coding exon 3) of the GRAP2 gene. This alteration results from a G to T substitution at nucleotide position 271, causing the aspartic acid (D) at amino acid position 91 to be replaced by a tyrosine (Y). 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	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D;.;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	.;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.1	M;.;M
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-7.2	D;D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.59	P;.;P
Vest4		0.64
MutPred		0.52		Gain of phosphorylation at D91 (P = 0.0343);Gain of phosphorylation at D91 (P = 0.0343);Gain of phosphorylation at D91 (P = 0.0343);
MVP		0.96
MPC		1.3
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2067102707; hg19: chr22-40356159;