rs78992879

chr5-73909872-C-Achr5-73909872-C-Gchr5-73909872-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001177693.2(ARHGEF28):c.4622C>A(p.Ala1541Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A1541G) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARHGEF28 NM_001177693.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.353

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08360025).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF28	NM_001177693.2	c.4622C>A	p.Ala1541Glu	missense_variant	34/36	ENST00000513042.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF28	ENST00000513042.7	c.4622C>A	p.Ala1541Glu	missense_variant	34/36	5	NM_001177693.2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152088 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1368802 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 674830

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152088 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74290

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	17
Dann	Benign	0.78
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.75	T;T;T;.;.;T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.084	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M;M;M;M;M;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.6	N;N;N;N;N;N;N
REVEL	Benign	0.14
Sift	Uncertain	0.0030	D;D;D;D;D;D;D
Sift4G	Uncertain	0.042	D;D;D;D;D;T;D
Polyphen		0.015	B;.;B;.;B;.;P
Vest4		0.17
MutPred		0.42		Gain of disorder (P = 0.0202);Gain of disorder (P = 0.0202);Gain of disorder (P = 0.0202);Gain of disorder (P = 0.0202);Gain of disorder (P = 0.0202);.;.;
MVP		0.095
MPC		0.12
ClinPred		0.18	T
GERP RS		3.4
Varity_R		0.083
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs78992879; hg19: chr5-73205697;