NM_001177693.2:c.374C>A

Variant names:

• chr5-73753101-C-A
• NM_001177693.2:c.374C>A

Variant summary

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

The NM_001177693.2(ARHGEF28):​c.374C>A​(p.Thr125Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,446,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ARHGEF28 NM_001177693.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.02

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=0.091064095).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF28	NM_001177693.2	c.374C>A	p.Thr125Lys	missense_variant	Exon 4 of 36	ENST00000513042.7	NP_001171164.1
ARHGEF28	NM_001080479.3	c.374C>A	p.Thr125Lys	missense_variant	Exon 4 of 37		NP_001073948.2
ARHGEF28	NM_001388078.1	c.374C>A	p.Thr125Lys	missense_variant	Exon 4 of 35		NP_001375007.1
ARHGEF28	NM_001388076.1	c.181+3117C>A		intron_variant	Intron 3 of 34		NP_001375005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF28	ENST00000513042.7	c.374C>A	p.Thr125Lys	missense_variant	Exon 4 of 36	5	NM_001177693.2	ENSP00000441436.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1446072 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 717800

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000406

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.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	14
DANN	Benign	0.69
DEOGEN2	Benign	0.011	.;.;T;.;T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.59	T;T;T;.;.
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.091	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.1	M;M;M;M;M
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.69	N;N;N;N;N
REVEL	Benign	0.017
Sift	Benign	0.48	T;T;T;T;T
Sift4G	Benign	0.21	T;T;T;T;T
Polyphen		0.016	B;.;B;.;B
Vest4		0.22
MutPred		0.40		Gain of ubiquitination at T125 (P = 0.017);Gain of ubiquitination at T125 (P = 0.017);Gain of ubiquitination at T125 (P = 0.017);Gain of ubiquitination at T125 (P = 0.017);Gain of ubiquitination at T125 (P = 0.017);
MVP		0.12
MPC		0.085
ClinPred		0.057	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.047
gMVP		0.47

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-73048926;