rs28940281

Variant names:

• chr8-1882669-C-T
• rs28940281
• NM_014629.4:c.995C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_014629.4(ARHGEF10):​c.995C>T​(p.Thr332Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000712 in 1,403,924 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as no classifications from unflagged records (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: ARHGEF10 NM_014629.4 missense
• Clinical Significance: no classifications from unflagged records no classifications from unflagged records P:1
• Conservation: PhyloP100: 7.17

Genes affected

ARHGEF10 (HGNC:14103): (Rho guanine nucleotide exchange factor 10) This gene encodes a Rho guanine nucleotide exchange factor (GEF). Rho GEFs regulate the activity of small Rho GTPases by stimulating the exchange of guanine diphosphate (GDP) for guanine triphosphate (GTP) and may play a role in neural morphogenesis. Mutations in this gene are associated with slowed nerve conduction velocity (SNCV). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

KBTBD11-OT1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-1882669-C-T is Pathogenic according to our data. Variant chr8-1882669-C-T is described in ClinVar as [no_classifications_from_unflagged_records]. Clinvar id is 2526.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1}. Variant chr8-1882669-C-T is described in UniProt as null. Variant chr8-1882669-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF10	NM_014629.4	c.995C>T	p.Thr332Ile	missense_variant	Exon 10 of 29	ENST00000349830.8	NP_055444.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF10	ENST00000349830.8	c.995C>T	p.Thr332Ile	missense_variant	Exon 10 of 29	1	NM_014629.4	ENSP00000340297.3
KBTBD11-OT1	ENST00000635855.1	n.*949C>T		non_coding_transcript_exon_variant	Exon 11 of 30	5		ENSP00000489726.1
KBTBD11-OT1	ENST00000635855.1	n.*949C>T		3_prime_UTR_variant	Exon 11 of 30	5		ENSP00000489726.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.12e-7 AC: 1 AN: 1403924 Hom.: 0 Cov.: 34 AF XY: 0.00000144 AC XY: 1 AN XY: 692754

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: 9.25e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: no classifications from unflagged records

Submissions summary: Pathogenic:1

Revision: no classifications from unflagged records

Submissions by phenotype

Autosomal dominant slowed nerve conduction velocity Pathogenic:1

Aug 26, 2011

OMIM

Significance: Pathogenic

Review Status: flagged submission

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	.;.;.;T;T;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.71	D;D;D;D;D;D
MetaSVM	Uncertain	-0.013	T
MutationAssessor	Pathogenic	3.0	.;.;M;M;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-4.3	D;D;D;D;N;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0010	D;D;D;D;T;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;.
Vest4		0.89
MutPred		0.33		.;.;Loss of phosphorylation at T357 (P = 0.0156);Loss of phosphorylation at T357 (P = 0.0156);.;.;
MVP		0.96
MPC		0.26
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.56
gMVP		0.55

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: rs28940281; hg19: chr8-1830835;