chr5-149620442-A-C

Position:

• chr5-149620442-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001001669.3(ARHGEF37):​c.983A>C​(p.His328Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000343 in 1,458,518 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ARHGEF37 NM_001001669.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.85

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF37	NM_001001669.3	c.983A>C	p.His328Pro	missense_variant	8/13	ENST00000333677.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF37	ENST00000333677.7	c.983A>C	p.His328Pro	missense_variant	8/13	2	NM_001001669.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000406 AC: 1 AN: 246340 Hom.: 0 AF XY: 0.00000748 AC XY: 1 AN XY: 133746

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000890

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1458518 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4 AN XY: 725604

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 2023

The c.983A>C (p.H328P) alteration is located in exon 8 (coding exon 7) of the ARHGEF37 gene. This alteration results from a A to C substitution at nucleotide position 983, causing the histidine (H) at amino acid position 328 to be replaced by a proline (P). 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	0.14
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Benign	0.62
DEOGEN2	Benign	0.053	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.061
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.29
Sift	Benign	0.14	T
Sift4G	Benign	0.12	T
Polyphen		0.35	B
Vest4		0.50
MutPred		0.70		Gain of helix (P = 0.2059);
MVP		0.41
MPC		0.22
ClinPred		0.21	T
GERP RS		6.1
Varity_R		0.41
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs755177143; hg19: chr5-149000005;