chr7-144187099-C-T

Variant names:

• chr7-144187099-C-T
• rs553072768
• NM_001003702.3:c.1285G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001003702.3(ARHGEF35):​c.1285G>A​(p.Val429Met) 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 0.00013 (1 hom., cov: 20)
  • Exomes 𝑓: 0.00019 (47 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARHGEF35 NM_001003702.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.224
• Publications: 2 publications found

Genes affected

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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.028370589).

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.1285G>A	p.Val429Met	missense	Exon 2 of 2	NP_001003702.2	A5YM69
	ARHGEF35	NM_001368318.1		c.1285G>A	p.Val429Met	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.1285G>A	p.Val429Met	missense	Exon 2 of 2	ENSP00000367355.3	A5YM69
	ARHGEF35	ENST00000688754.1		c.1285G>A	p.Val429Met	missense	Exon 2 of 2	ENSP00000510684.1	A5YM69
	ARHGEF35	ENST00000852510.1		c.1285G>A	p.Val429Met	missense	Exon 3 of 3	ENSP00000522569.1

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 18 AN: 136554 Hom.: 1 Cov.: 20

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000179

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000165 AC: 37 AN: 223632 AF XY: 0.000189

Gnomad AFR exome AF: 0.000233

Gnomad AMR exome AF: 0.000183

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.000183

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000194 AC: 271 AN: 1399230 Hom.: 47 Cov.: 31 AF XY: 0.000198 AC XY: 138 AN XY: 696664

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

African (AFR) AF: 0.000217 AC: 7 AN: 32318

American (AMR) AF: 0.000228 AC: 10 AN: 43844

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25768

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39640

South Asian (SAS) AF: 0.000105 AC: 9 AN: 85610

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50116

Middle Eastern (MID) AF: 0.000180 AC: 1 AN: 5568

European-Non Finnish (NFE) AF: 0.000216 AC: 229 AN: 1058080

Other (OTH) AF: 0.000120 AC: 7 AN: 58286

⚠️ 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 AF: 0.000132 AC: 18 AN: 136662 Hom.: 1 Cov.: 20 AF XY: 0.0000901 AC XY: 6 AN XY: 66576

African (AFR) AF: 0.000192 AC: 7 AN: 36384

American (AMR) AF: 0.00 AC: 0 AN: 13922

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3336

East Asian (EAS) AF: 0.00 AC: 0 AN: 5040

South Asian (SAS) AF: 0.00 AC: 0 AN: 4540

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8968

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.000179 AC: 11 AN: 61422

Other (OTH) AF: 0.00 AC: 0 AN: 1886

Alfa AF: 0.000422 Hom.: 1

ExAC AF: 0.000111 AC: 13

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	0.10
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.030
DANN	Benign	0.87
DEOGEN2	Benign	0.0082	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0011	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.97	N
PhyloP100		-0.22
PROVEAN	Benign	0.20	N
REVEL	Benign	0.011
Sift	Benign	0.84	T
Sift4G	Benign	0.16	T
Polyphen		0.35	B
Vest4		0.021
MutPred		0.29		Loss of sheet (P = 0.0104)
MVP		0.040
MPC		1.2
ClinPred		0.0051	T
GERP RS		-3.3
Varity_R		0.023
gMVP		0.021
Mutation Taster		=98/2	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: rs553072768; hg19: chr7-143884192;