5-149616754-C-T

Variant names:

• chr5-149616754-C-T
• rs374655369
• NM_001001669.3:c.646C>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.646C>T​(p.Arg216Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000824 in 1,601,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R216H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: ARHGEF37 NM_001001669.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.59
• Publications: 3 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=0.097767025).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF37	NM_001001669.3	c.646C>T	p.Arg216Cys	missense_variant	Exon 5 of 13	ENST00000333677.7	NP_001001669.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF37	ENST00000333677.7	c.646C>T	p.Arg216Cys	missense_variant	Exon 5 of 13	2	NM_001001669.3	ENSP00000328083.6

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000121 AC: 30 AN: 247696 AF XY: 0.0000967

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.0000587

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000223

Gnomad FIN exome AF: 0.000418

Gnomad NFE exome AF: 0.0000801

Gnomad OTH exome AF: 0.000501

GnomAD4 exome AF: 0.0000711 AC: 103 AN: 1448986 Hom.: 0 Cov.: 31 AF XY: 0.0000682 AC XY: 49 AN XY: 718332

African (AFR) AF: 0.000150 AC: 5 AN: 33278

American (AMR) AF: 0.0000451 AC: 2 AN: 44352

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25912

East Asian (EAS) AF: 0.000102 AC: 4 AN: 39380

South Asian (SAS) AF: 0.0000351 AC: 3 AN: 85430

European-Finnish (FIN) AF: 0.000714 AC: 38 AN: 53236

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5724

European-Non Finnish (NFE) AF: 0.0000381 AC: 42 AN: 1101912

Other (OTH) AF: 0.000134 AC: 8 AN: 59762

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74300

African (AFR) AF: 0.000434 AC: 18 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.000378 AC: 4 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68032

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000148 Hom.: 0

Bravo AF: 0.000136

ESP6500AA AF: 0.000766 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000149 AC: 18

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.646C>T (p.R216C) alteration is located in exon 5 (coding exon 4) of the ARHGEF37 gene. This alteration results from a C to T substitution at nucleotide position 646, causing the arginine (R) at amino acid position 216 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	0.15
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.098	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		3.6
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Benign	0.13
Sift	Benign	0.12	T
Sift4G	Benign	0.12	T
Polyphen		0.35	B
Vest4		0.46
MVP		0.22
MPC		0.15
ClinPred		0.13	T
GERP RS		5.4
Varity_R		0.42
gMVP		0.57
Mutation Taster		=83/17	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: rs374655369; hg19: chr5-148996317; COSMIC: COSV61368907;