5-73780686-C-T

Position:

• chr5-73780686-C-T

Variant summary

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

The NM_001177693.2(ARHGEF28):​c.851C>T​(p.Pro284Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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. P284Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARHGEF28 NM_001177693.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.90

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]

ENSG00000249293 (HGNC:):

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=0.04796645).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF28	NM_001177693.2	c.851C>T	p.Pro284Leu	missense_variant	7/36	ENST00000513042.7	NP_001171164.1
ARHGEF28	NM_001080479.3	c.851C>T	p.Pro284Leu	missense_variant	7/37		NP_001073948.2
ARHGEF28	NM_001388078.1	c.851C>T	p.Pro284Leu	missense_variant	7/35		NP_001375007.1
ARHGEF28	NM_001388076.1	c.557C>T	p.Pro186Leu	missense_variant	6/35		NP_001375005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF28	ENST00000513042.7	c.851C>T	p.Pro284Leu	missense_variant	7/36	5	NM_001177693.2	ENSP00000441436.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1403194 Hom.: 0 Cov.: 41 AF XY: 0.00 AC XY: 0 AN XY: 692480

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 Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Benign	0.0032	.;.;T;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.27	T;T;T;.;.
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.048	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.88	N;N;N;N;N
REVEL	Benign	0.082
Sift	Benign	0.26	T;T;T;T;T
Sift4G	Benign	0.20	T;T;T;T;T
Polyphen		0.0010	B;.;B;.;B
Vest4		0.054
MutPred		0.27		Gain of helix (P = 0.0082);Gain of helix (P = 0.0082);Gain of helix (P = 0.0082);Gain of helix (P = 0.0082);Gain of helix (P = 0.0082);
MVP		0.12
MPC		0.071
ClinPred		0.073	T
GERP RS		-0.022
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.047
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs6453022; hg19: chr5-73076511;