chr5-149621988-A-C

Position:

• chr5-149621988-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001001669.3(ARHGEF37):​c.1261A>C​(p.Met421Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.387 in 1,613,668 control chromosomes in the GnomAD database, including 123,658 homozygotes. 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.39 (11640 hom., cov: 33)
  • Exomes 𝑓: 0.39 (112018 hom.)
• Consequence: ARHGEF37 NM_001001669.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.136

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2713671E-4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.501 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF37	NM_001001669.3	c.1261A>C	p.Met421Leu	missense_variant	9/13	ENST00000333677.7	NP_001001669.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF37	ENST00000333677.7	c.1261A>C	p.Met421Leu	missense_variant	9/13	2	NM_001001669.3	ENSP00000328083	P1

Frequencies

GnomAD3 genomes AF: 0.389 AC: 59056 AN: 151972 Hom.: 11630 Cov.: 33

Gnomad AFR AF: 0.384

Gnomad AMI AF: 0.506

Gnomad AMR AF: 0.452

Gnomad ASJ AF: 0.313

Gnomad EAS AF: 0.519

Gnomad SAS AF: 0.514

Gnomad FIN AF: 0.345

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.369

Gnomad OTH AF: 0.367

GnomAD3 exomes AF: 0.417 AC: 103500 AN: 248334 Hom.: 22550 AF XY: 0.414 AC XY: 55770 AN XY: 134760

Gnomad AFR exome AF: 0.388

Gnomad AMR exome AF: 0.533

Gnomad ASJ exome AF: 0.304

Gnomad EAS exome AF: 0.504

Gnomad SAS exome AF: 0.511

Gnomad FIN exome AF: 0.353

Gnomad NFE exome AF: 0.370

Gnomad OTH exome AF: 0.387

GnomAD4 exome AF: 0.387 AC: 565478 AN: 1461578 Hom.: 112018 Cov.: 61 AF XY: 0.389 AC XY: 283014 AN XY: 727058

Gnomad4 AFR exome AF: 0.385

Gnomad4 AMR exome AF: 0.525

Gnomad4 ASJ exome AF: 0.307

Gnomad4 EAS exome AF: 0.518

Gnomad4 SAS exome AF: 0.506

Gnomad4 FIN exome AF: 0.361

Gnomad4 NFE exome AF: 0.371

Gnomad4 OTH exome AF: 0.381

GnomAD4 genome AF: 0.389 AC: 59114 AN: 152090 Hom.: 11640 Cov.: 33 AF XY: 0.393 AC XY: 29216 AN XY: 74326

Gnomad4 AFR AF: 0.385

Gnomad4 AMR AF: 0.453

Gnomad4 ASJ AF: 0.313

Gnomad4 EAS AF: 0.517

Gnomad4 SAS AF: 0.512

Gnomad4 FIN AF: 0.345

Gnomad4 NFE AF: 0.369

Gnomad4 OTH AF: 0.368

Alfa AF: 0.370 Hom.: 25850

Bravo AF: 0.396

TwinsUK AF: 0.363 AC: 1346

ALSPAC AF: 0.367 AC: 1416

ESP6500AA AF: 0.381 AC: 1617

ESP6500EA AF: 0.355 AC: 3010

ExAC AF: 0.414 AC: 50168

Asia WGS AF: 0.498 AC: 1732 AN: 3478

EpiCase AF: 0.360

EpiControl AF: 0.351

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	9.6
DANN	Benign	0.54
DEOGEN2	Benign	0.0043	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.00013	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-3.1	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.78	N
REVEL	Benign	0.17
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.058
MutPred		0.20		Loss of MoRF binding (P = 0.0817);
MPC		0.084
ClinPred		0.0017	T
GERP RS		4.1
Varity_R		0.11
gMVP		0.17

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

Publications

LitVar

Other links and lift over

dbSNP: rs4629585; hg19: chr5-149001551; COSMIC: COSV61369027; COSMIC: COSV61369027;