17-12952541-G-A

Variant summary

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

The NM_014859.6(ARHGAP44):c.1096G>A(p.Ala366Thr) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARHGAP44 NM_014859.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.13

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12661442).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGAP44	NM_014859.6	c.1096G>A	p.Ala366Thr	missense_variant	13/21	ENST00000379672.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGAP44	ENST00000379672.10	c.1096G>A	p.Ala366Thr	missense_variant	13/21	1	NM_014859.6	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1428626 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 707052

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

May 27, 2022

The c.1096G>A (p.A366T) alteration is located in exon 13 (coding exon 13) of the ARHGAP44 gene. This alteration results from a G to A substitution at nucleotide position 1096, causing the alanine (A) at amino acid position 366 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	0.086
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	23
Dann	Benign	0.94
DEOGEN2	Benign	0.038	T;.;T;T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.23	N;N;.;.
MutationTaster	Benign	0.91	D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.22	N;N;.;.
REVEL	Benign	0.054
Sift	Benign	0.54	T;T;.;.
Sift4G	Benign	0.69	T;T;T;T
Polyphen		0.0050	B;.;.;.
Vest4		0.17
MutPred		0.46		Loss of MoRF binding (P = 0.1399);Loss of MoRF binding (P = 0.1399);Loss of MoRF binding (P = 0.1399);.;
MVP		0.068
MPC		0.67
ClinPred		0.23	T
GERP RS		4.8
Varity_R		0.080
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr17-12855858;