chr5-149597944-C-T

Variant names:

• chr5-149597944-C-T
• rs200527896
• NM_001001669.3:c.175C>T

Variant summary

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

The NM_001001669.3(ARHGEF37):​c.175C>T​(p.Arg59Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000698 in 1,591,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R59L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000073 (0 hom.)
• Consequence: ARHGEF37 NM_001001669.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.44
• Publications: 1 publications found

Genes affected

ARHGEF37 (HGNC:34430): (Rho guanine nucleotide exchange factor 37) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of catalytic activity. Predicted to be located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.088771105).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF37	NM_001001669.3	c.175C>T	p.Arg59Cys	missense_variant	Exon 2 of 13	ENST00000333677.7	NP_001001669.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF37	ENST00000333677.7	c.175C>T	p.Arg59Cys	missense_variant	Exon 2 of 13	2	NM_001001669.3	ENSP00000328083.6
ARHGEF37	ENST00000505810.5	c.175C>T	p.Arg59Cys	missense_variant	Exon 2 of 3	5		ENSP00000425621.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000617 AC: 13 AN: 210632 AF XY: 0.0000524

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000800

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000730 AC: 105 AN: 1438766 Hom.: 0 Cov.: 30 AF XY: 0.0000742 AC XY: 53 AN XY: 714328

African (AFR) AF: 0.00 AC: 0 AN: 32590

American (AMR) AF: 0.00 AC: 0 AN: 40700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25592

East Asian (EAS) AF: 0.00115 AC: 44 AN: 38276

South Asian (SAS) AF: 0.0000972 AC: 8 AN: 82304

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.0000463 AC: 51 AN: 1101722

Other (OTH) AF: 0.0000336 AC: 2 AN: 59578

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74452

African (AFR) AF: 0.00 AC: 0 AN: 41552

American (AMR) AF: 0.0000654 AC: 1 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000271 Hom.: 2

Bravo AF: 0.0000642

ExAC AF: 0.0000414 AC: 5

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.175C>T (p.R59C) alteration is located in exon 2 (coding exon 1) of the ARHGEF37 gene. This alteration results from a C to T substitution at nucleotide position 175, causing the arginine (R) at amino acid position 59 to be replaced by a cysteine (C). 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	0.088
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.0096	.;T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.089	T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.7	.;L
PhyloP100		1.4
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.070	N;N
REVEL	Benign	0.26
Sift	Uncertain	0.013	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		1.0	.;D
Vest4		0.29
MVP		0.52
MPC		0.14
ClinPred		0.23	T
GERP RS		5.6
Varity_R		0.16
gMVP		0.19
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs200527896; hg19: chr5-148977507;