17-12958727-C-G

Position:

• chr17-12958727-C-G

Variant summary

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

The ENST00000379672.10(ARHGAP44):​c.1353C>G​(p.Phe451Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARHGAP44 ENST00000379672.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.75

Genes affected

ARHGAP44 (HGNC:29096): (Rho GTPase activating protein 44) Enables phospholipid binding activity. Predicted to be involved in several processes, including modification of dendritic spine; negative regulation of Rac protein signal transduction; and regulation of plasma membrane bounded cell projection organization. Located in leading edge membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGAP44	NM_014859.6	c.1353C>G	p.Phe451Leu	missense_variant	16/21	ENST00000379672.10	NP_055674.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGAP44	ENST00000379672.10	c.1353C>G	p.Phe451Leu	missense_variant	16/21	1	NM_014859.6	ENSP00000368994	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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 23, 2024

The c.1353C>G (p.F451L) alteration is located in exon 16 (coding exon 16) of the ARHGAP44 gene. This alteration results from a C to G substitution at nucleotide position 1353, causing the phenylalanine (F) at amino acid position 451 to be replaced by a leucine (L). 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	1.0
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T;.;T;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Benign	0.070	D
MetaRNN	Uncertain	0.64	D;D;D;D
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.7	M;M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.3	D;D;.;.
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D;D;.;.
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.75
MutPred		0.38		Gain of glycosylation at T454 (P = 0.2132);Gain of glycosylation at T454 (P = 0.2132);Gain of glycosylation at T454 (P = 0.2132);.;
MVP		0.28
MPC		1.9
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.90
gMVP		0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-12862044;