7-144187438-C-A

Variant names:

• chr7-144187438-C-A
• rs996964688
• NM_001003702.3:c.946G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001003702.3(ARHGEF35):​c.946G>T​(p.Gly316Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G316R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 15)
  • Exomes 𝑓: 0.0000011 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARHGEF35 NM_001003702.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0810
• Publications: 0 publications found

Genes affected

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1616031).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001003702.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF35	NM_001003702.3	MANE Select	c.946G>T	p.Gly316Cys	missense	Exon 2 of 2	NP_001003702.2	A5YM69
	ARHGEF35	NM_001368318.1		c.946G>T	p.Gly316Cys	missense	Exon 2 of 2	NP_001355247.1	A5YM69

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF35	ENST00000378115.3	TSL:1 MANE Select	c.946G>T	p.Gly316Cys	missense	Exon 2 of 2	ENSP00000367355.3	A5YM69
	ARHGEF35	ENST00000688754.1		c.946G>T	p.Gly316Cys	missense	Exon 2 of 2	ENSP00000510684.1	A5YM69
	ARHGEF35	ENST00000852510.1		c.946G>T	p.Gly316Cys	missense	Exon 3 of 3	ENSP00000522569.1

Frequencies

GnomAD3 genomes Cov.: 15

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000109 AC: 1 AN: 915382 Hom.: 0 Cov.: 15 AF XY: 0.00 AC XY: 0 AN XY: 466410

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23278

American (AMR) AF: 0.00 AC: 0 AN: 27098

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21120

East Asian (EAS) AF: 0.00 AC: 0 AN: 33176

South Asian (SAS) AF: 0.00 AC: 0 AN: 60926

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47094

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2974

European-Non Finnish (NFE) AF: 0.00000152 AC: 1 AN: 658426

Other (OTH) AF: 0.00 AC: 0 AN: 41290

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 15

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	12
DANN	Benign	0.81
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PhyloP100		-0.081
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.047
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.048	D
Polyphen		1.0	D
Vest4		0.14
MutPred		0.19		Loss of relative solvent accessibility (P = 0.0071)
MVP		0.30
MPC		1.2
ClinPred		0.70	D
GERP RS		-3.4
Varity_R		0.31
gMVP		0.0085
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs996964688; hg19: chr7-143884531;