Genetic Variant NM_014629.4:c.37+5C>A (chr8-1843441-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014629.4(ARHGEF10):c.37+5C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ARHGEF10
NM_014629.4 splice_region, intron

Scores

Splicing: ADA: 0.00001287

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0420

Publications

0 publications found

Variant links:

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]

ARHGEF10 Gene-Disease associations (from GenCC):

autosomal dominant slowed nerve conduction velocity
Inheritance: AD, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
hereditary peripheral neuropathy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
peripheral neuropathy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ARHGEF10 links:

KBTBD11-OT1 (HGNC:):

KBTBD11-OT1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014629.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ARHGEF10	NM_014629.4	MANE Select	c.37+5C>A	splice_region intron	N/A	NP_055444.2	O15013-5
ARHGEF10	NM_001438091.1		c.37+5C>A	splice_region intron	N/A	NP_001425020.1
ARHGEF10	NM_001308153.3		c.37+5C>A	splice_region intron	N/A	NP_001295082.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ARHGEF10	ENST00000349830.8	TSL:1 MANE Select	c.37+5C>A	splice_region intron	N/A	ENSP00000340297.3	O15013-5
ARHGEF10	ENST00000518288.5	TSL:1	c.109+5C>A	splice_region intron	N/A	ENSP00000431012.1	O15013-6
ARHGEF10	ENST00000520359.5	TSL:1	c.37+5C>A	splice_region intron	N/A	ENSP00000427909.1	O15013-7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

248776

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459230

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726008

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33428

American (AMR)

AF:

0.00

AC:

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86116

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5672

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110572

Other (OTH)

AF:

0.0000166

AC:

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

2.4

(source)

DANN

Benign

0.73

PhyloP100

0.042

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000013

dbscSNV1_RF

Benign

0.010

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over