17-29575666-T-G

Position:

• chr17-29575666-T-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_014030.4(GIT1):​c.1790A>C​(p.Asp597Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,460,430 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: GIT1 NM_014030.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.46

Genes affected

GIT1 (HGNC:4272): (GIT ArfGAP 1) Enables gamma-tubulin binding activity. Involved in positive regulation of microtubule nucleation and regulation of cytokinesis. Located in several cellular components, including focal adhesion; microtubule cytoskeleton; and mitochondrion. Implicated in attention deficit hyperactivity disorder. Biomarker of Huntington's disease. [provided by Alliance of Genome Resources, Apr 2022]

ABHD15-AS1 (HGNC:49685): (ABHD15 antisense RNA 1)

TP53I13 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GIT1	NM_014030.4	c.1790A>C	p.Asp597Ala	missense_variant	17/20	ENST00000225394.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GIT1	ENST00000225394.8	c.1790A>C	p.Asp597Ala	missense_variant	17/20	1	NM_014030.4	A1
ABHD15-AS1	ENST00000581474.1	n.153+14967T>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460430 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 726536

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2023

The c.1817A>C (p.D606A) alteration is located in exon 18 (coding exon 18) of the GIT1 gene. This alteration results from a A to C substitution at nucleotide position 1817, causing the aspartic acid (D) at amino acid position 606 to be replaced by an alanine (A). 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	0.78
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;.;.;.;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.57	D;D;D;D;D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Benign	0.81	L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.2	D;D;.;.;.
REVEL	Uncertain	0.51
Sift	Uncertain	0.0030	D;D;.;.;.
Sift4G	Uncertain	0.0070	D;D;T;D;D
Polyphen		1.0	D;D;.;.;.
Vest4		0.56
MutPred		0.16		Gain of glycosylation at T601 (P = 0.1848);.;.;Gain of glycosylation at T601 (P = 0.1848);.;
MVP		0.79
MPC		1.7
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.60
gMVP		0.80

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: rs1028315192; hg19: chr17-27902684;