17-12955957-C-G

Position:

• chr17-12955957-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014859.6(ARHGAP44):​c.1227C>G​(p.Asn409Lys) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ARHGAP44 NM_014859.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.51

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]

ARHGAP44 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGAP44	NM_014859.6	c.1227C>G	p.Asn409Lys	missense_variant	14/21	ENST00000379672.10	NP_055674.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGAP44	ENST00000379672.10	c.1227C>G	p.Asn409Lys	missense_variant	14/21	1	NM_014859.6	ENSP00000368994.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

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

Mar 25, 2024

The c.1227C>G (p.N409K) alteration is located in exon 14 (coding exon 14) of the ARHGAP44 gene. This alteration results from a C to G substitution at nucleotide position 1227, causing the asparagine (N) at amino acid position 409 to be replaced by a lysine (K). 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	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Benign	0.88
DEOGEN2	Benign	0.36	T;.;T;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Benign	0.046	D
MetaRNN	Pathogenic	0.82	D;D;D;D
MetaSVM	Benign	-0.76	T
MutationAssessor	Pathogenic	4.0	H;H;.;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.5	D;D;.;.
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	D;D;.;.
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.99
MutPred		0.73		Gain of ubiquitination at N409 (P = 0.0408);Gain of ubiquitination at N409 (P = 0.0408);Gain of ubiquitination at N409 (P = 0.0408);.;
MVP		0.21
MPC		1.8
ClinPred		1.0	D
GERP RS		1.4
Varity_R		0.78
gMVP		0.96

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: chr17-12859274;