chr5-73923129-C-G

Variant names:

• chr5-73923129-C-G
• ENST00000437974.5:c.4991C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001080479.3(ARHGEF28):​c.4991C>G​(p.Pro1664Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,383,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. P1664L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ARHGEF28 NM_001080479.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.00

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.027904212).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF28	NM_001177693.2	c.4948+11554C>G		intron_variant	Intron 35 of 35	ENST00000513042.7	NP_001171164.1
ARHGEF28	NM_001080479.3	c.4991C>G	p.Pro1664Arg	missense_variant	Exon 36 of 37		NP_001073948.2
ARHGEF28	NM_001388076.1	c.4654+11554C>G		intron_variant	Intron 34 of 34		NP_001375005.1
ARHGEF28	NM_001244364.2	c.4009+11554C>G		intron_variant	Intron 27 of 27		NP_001231293.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF28	ENST00000513042.7	c.4948+11554C>G		intron_variant	Intron 35 of 35	5	NM_001177693.2	ENSP00000441436.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1383538 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 682716

Gnomad4 AFR exome AF: 0.0000317

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: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.12
DANN	Benign	0.78
DEOGEN2	Benign	0.0047	.;.;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.00077	N
LIST_S2	Benign	0.43	T;.;T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.028	T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.17	T
PROVEAN	Benign	-0.21	N;N;N
REVEL	Benign	0.0030
Sift	Benign	0.51	T;T;T
Sift4G	Benign	0.064	T;T;D
Polyphen		0.0	.;.;B
Vest4		0.081
MutPred		0.18		.;.;Loss of catalytic residue at P583 (P = 0.0131);
MVP		0.055
MPC		0.074
ClinPred		0.039	T
GERP RS		-6.6
gMVP		0.13

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-73218954;