11-46680720-C-G

Position:

• chr11-46680720-C-G

Variant summary

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

The NM_004308.5(ARHGAP1):​c.663G>C​(p.Gln221His) 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: 32)
• Consequence: ARHGAP1 NM_004308.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.89

Genes affected

ARHGAP1 (HGNC:673): (Rho GTPase activating protein 1) This gene encodes a member of a large family of proteins that activate Rho-type guanosine triphosphate (GTP) metabolizing enzymes. The encoded protein contains a SRC homology 3 domain and interacts with Bcl-2-associated protein family members. [provided by RefSeq, Aug 2012]

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=0.12751761).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGAP1	NM_004308.5	c.663G>C	p.Gln221His	missense_variant	8/13	ENST00000311956.9	NP_004299.1
ARHGAP1	XM_047426933.1	c.663G>C	p.Gln221His	missense_variant	8/13		XP_047282889.1
ARHGAP1	XM_024448520.2	c.531G>C	p.Gln177His	missense_variant	7/12		XP_024304288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGAP1	ENST00000311956.9	c.663G>C	p.Gln221His	missense_variant	8/13	1	NM_004308.5	ENSP00000310491	P1
ARHGAP1	ENST00000526423.1	n.351G>C		non_coding_transcript_exon_variant	3/8	1
ARHGAP1	ENST00000528837.5	c.525G>C	p.Gln175His	missense_variant	6/11	5		ENSP00000434883

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

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

Jun 18, 2021

The c.663G>C (p.Q221H) alteration is located in exon 8 (coding exon 7) of the ARHGAP1 gene. This alteration results from a G to C substitution at nucleotide position 663, causing the glutamine (Q) at amino acid position 221 to be replaced by a histidine (H). 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	0.11
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	18
DANN	Benign	0.88
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.070
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.52	N
MutationTaster	Benign	0.96	D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	0.36	N
REVEL	Benign	0.040
Sift	Benign	0.66	T
Sift4G	Benign	0.60	T
Polyphen		0.0020	B
Vest4		0.32
MutPred		0.24		Gain of catalytic residue at K222 (P = 0.071);
MVP		0.31
MPC		0.25
ClinPred		0.38	T
GERP RS		4.0
Varity_R		0.055
gMVP		0.53

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: chr11-46702270;