NM_001003702.3:c.1027G>A

Variant names:

• chr7-144187357-C-T
• rs1465837045
• NM_001003702.3:c.1027G>A

Variant summary

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

The NM_001003702.3(ARHGEF35):​c.1027G>A​(p.Glu343Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000032 (0 hom., cov: 17)
  • Exomes 𝑓: 0.000017 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARHGEF35 NM_001003702.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.51
• Publications: 1 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=0.07489005).

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.1027G>A	p.Glu343Lys	missense	Exon 2 of 2	NP_001003702.2	A5YM69
	ARHGEF35	NM_001368318.1		c.1027G>A	p.Glu343Lys	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.1027G>A	p.Glu343Lys	missense	Exon 2 of 2	ENSP00000367355.3	A5YM69
	ARHGEF35	ENST00000688754.1		c.1027G>A	p.Glu343Lys	missense	Exon 2 of 2	ENSP00000510684.1	A5YM69
	ARHGEF35	ENST00000852510.1		c.1027G>A	p.Glu343Lys	missense	Exon 3 of 3	ENSP00000522569.1

Frequencies

GnomAD3 genomes AF: 0.0000321 AC: 4 AN: 124800 Hom.: 0 Cov.: 17

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000669

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000174

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000174 AC: 23 AN: 1323548 Hom.: 2 Cov.: 29 AF XY: 0.0000166 AC XY: 11 AN XY: 662016

African (AFR) AF: 0.00 AC: 0 AN: 30870

American (AMR) AF: 0.00 AC: 0 AN: 41788

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25494

East Asian (EAS) AF: 0.00 AC: 0 AN: 38926

South Asian (SAS) AF: 0.00 AC: 0 AN: 81950

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3934

European-Non Finnish (NFE) AF: 0.0000231 AC: 23 AN: 994378

Other (OTH) AF: 0.00 AC: 0 AN: 55652

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000320 AC: 4 AN: 124886 Hom.: 0 Cov.: 17 AF XY: 0.0000166 AC XY: 1 AN XY: 60186

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

African (AFR) AF: 0.00 AC: 0 AN: 32602

American (AMR) AF: 0.00 AC: 0 AN: 12420

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3294

East Asian (EAS) AF: 0.000671 AC: 3 AN: 4470

South Asian (SAS) AF: 0.00 AC: 0 AN: 3718

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8006

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 266

European-Non Finnish (NFE) AF: 0.0000174 AC: 1 AN: 57576

Other (OTH) AF: 0.00 AC: 0 AN: 1702

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000281198), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.41
DANN	Benign	0.54
DEOGEN2	Benign	0.028	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0039	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.075	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N
PhyloP100		-1.5
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.082
Sift	Benign	0.60	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.93	P
Vest4		0.091
MutPred		0.24		Gain of ubiquitination at E343 (P = 6e-04)
MVP		0.040
MPC		1.3
ClinPred		0.13	T
GERP RS		-0.67
Varity_R		0.039
gMVP		0.019
Mutation Taster		=100/0	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: rs1465837045; hg19: chr7-143884450; COSMIC: COSV100967669; COSMIC: COSV100967669;