chr8-1857947-TTTTTC-T

Variant names:

• chr8-1857947-TTTTTC-T
• rs200470716
• NM_014629.4:c.38-8_38-4delCTTTT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_014629.4(ARHGEF10):​c.38-8_38-4delCTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00498 in 1,610,914 control chromosomes in the GnomAD database, including 64 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0043 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (57 hom.)
• Consequence: ARHGEF10 NM_014629.4 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.32
• Publications: 0 publications found

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

KBTBD11-OT1 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 8-1857947-TTTTTC-T is Benign according to our data. Variant chr8-1857947-TTTTTC-T is described in ClinVar as Benign. ClinVar VariationId is 708928.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00505 (7374/1458830) while in subpopulation SAS AF = 0.0167 (1438/86140). AF 95% confidence interval is 0.016. There are 57 homozygotes in GnomAdExome4. There are 4018 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.
• BS2: High AC in GnomAd4 at 648 Unknown,AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF10	NM_014629.4	MANE Select	c.38-8_38-4delCTTTT		splice_region intron	N/A	NP_055444.2	O15013-5
	ARHGEF10	NM_001438091.1		c.38-8_38-4delCTTTT		splice_region intron	N/A	NP_001425020.1
	ARHGEF10	NM_001308153.3		c.38-8_38-4delCTTTT		splice_region intron	N/A	NP_001295082.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF10	ENST00000349830.8	TSL:1 MANE Select	c.38-12_38-8delTTTTC		splice_region intron	N/A	ENSP00000340297.3	O15013-5
	ARHGEF10	ENST00000518288.5	TSL:1	c.110-12_110-8delTTTTC		splice_region intron	N/A	ENSP00000431012.1	O15013-6
	ARHGEF10	ENST00000520359.5	TSL:1	c.38-12_38-8delTTTTC		splice_region intron	N/A	ENSP00000427909.1	O15013-7

Frequencies

GnomAD3 genomes AF: 0.00426 AC: 647 AN: 151966 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.000846

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00479

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0129

Gnomad FIN AF: 0.0133

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00472

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00599 AC: 1502 AN: 250580 AF XY: 0.00671

Gnomad AFR exome AF: 0.000743

Gnomad AMR exome AF: 0.00272

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.000436

Gnomad FIN exome AF: 0.0120

Gnomad NFE exome AF: 0.00533

Gnomad OTH exome AF: 0.00800

GnomAD4 exome AF: 0.00505 AC: 7374 AN: 1458830 Hom.: 57 AF XY: 0.00553 AC XY: 4018 AN XY: 725974

African (AFR) AF: 0.000628 AC: 21 AN: 33424

American (AMR) AF: 0.00259 AC: 116 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.000421 AC: 11 AN: 26098

East Asian (EAS) AF: 0.000328 AC: 13 AN: 39652

South Asian (SAS) AF: 0.0167 AC: 1438 AN: 86140

European-Finnish (FIN) AF: 0.0123 AC: 656 AN: 53386

Middle Eastern (MID) AF: 0.0142 AC: 82 AN: 5762

European-Non Finnish (NFE) AF: 0.00426 AC: 4729 AN: 1109330

Other (OTH) AF: 0.00511 AC: 308 AN: 60324

GnomAD4 genome AF: 0.00426 AC: 648 AN: 152084 Hom.: 7 Cov.: 32 AF XY: 0.00452 AC XY: 336 AN XY: 74362

African (AFR) AF: 0.000843 AC: 35 AN: 41498

American (AMR) AF: 0.00478 AC: 73 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5158

South Asian (SAS) AF: 0.0131 AC: 63 AN: 4814

European-Finnish (FIN) AF: 0.0133 AC: 141 AN: 10590

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00472 AC: 321 AN: 67964

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00299 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	ARHGEF10-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs200470716; hg19: chr8-1806113;