7-144187189-C-T

Position:

• chr7-144187189-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001003702.3(ARHGEF35):​c.1195G>A​(p.Glu399Lys) 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. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 19)
• Consequence: ARHGEF35 NM_001003702.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.830

Genes affected

ARHGEF35 (HGNC:33846): (Rho guanine nucleotide exchange factor 35)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.046495706).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF35	NM_001003702.3	c.1195G>A	p.Glu399Lys	missense_variant	2/2	ENST00000378115.3	NP_001003702.2
ARHGEF35	NM_001368318.1	c.1195G>A	p.Glu399Lys	missense_variant	2/2		NP_001355247.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF35	ENST00000378115.3	c.1195G>A	p.Glu399Lys	missense_variant	2/2	1	NM_001003702.3	ENSP00000367355.3
ARHGEF35	ENST00000688754.1	c.1195G>A	p.Glu399Lys	missense_variant	2/2			ENSP00000510684.1

Frequencies

GnomAD3 genomes Cov.: 19

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 19

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 27, 2023

The c.1195G>A (p.E399K) alteration is located in exon 2 (coding exon 1) of the ARHGEF35 gene. This alteration results from a G to A substitution at nucleotide position 1195, causing the glutamic acid (E) at amino acid position 399 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	Benign	0.12
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.033	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0016	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.0070
Sift	Benign	0.094	T
Sift4G	Uncertain	0.017	D
Polyphen		0.087	B
Vest4		0.11
MutPred		0.25		Gain of ubiquitination at E399 (P = 0.0029);
MVP		0.040
MPC		1.3
ClinPred		0.10	T
GERP RS		-1.1
Varity_R		0.059
gMVP		0.018

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: chr7-143884282;