5-73749949-G-C

Variant names:

• chr5-73749949-G-C
• rs562632840
• NM_001177693.2:c.146G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001177693.2(ARHGEF28):​c.146G>C​(p.Arg49Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ARHGEF28 NM_001177693.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.79

Genes affected

ARHGEF28 (HGNC:30322): (Rho guanine nucleotide exchange factor 28) This gene encodes a member of the Rho guanine nucleotide exchange factor family. The encoded protein interacts with low molecular weight neurofilament mRNA and may be involved in the formation of amyotrophic lateral sclerosis neurofilament aggregates. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33349353).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF28	NM_001177693.2	c.146G>C	p.Arg49Pro	missense_variant	Exon 3 of 36	ENST00000513042.7	NP_001171164.1
ARHGEF28	NM_001080479.3	c.146G>C	p.Arg49Pro	missense_variant	Exon 3 of 37		NP_001073948.2
ARHGEF28	NM_001388078.1	c.146G>C	p.Arg49Pro	missense_variant	Exon 3 of 35		NP_001375007.1
ARHGEF28	NM_001388076.1	c.146G>C	p.Arg49Pro	missense_variant	Exon 3 of 35		NP_001375005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF28	ENST00000513042.7	c.146G>C	p.Arg49Pro	missense_variant	Exon 3 of 36	5	NM_001177693.2	ENSP00000441436.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248742 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134948

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: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461580 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727076

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000826 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	.;.;T;.;.;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.83	T;T;T;T;.;.
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.33	T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.5	M;M;M;.;M;M
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.2	N;N;N;D;N;N
REVEL	Benign	0.20
Sift	Uncertain	0.0020	D;D;D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;.;D
Vest4		0.67
MutPred		0.40		Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);
MVP		0.62
MPC		0.50
ClinPred		0.87	D
GERP RS		5.3
Varity_R		0.32
gMVP		0.79

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: rs562632840; hg19: chr5-73045774;