1-17607948-G-C

Variant names:

• chr1-17607948-G-C
• rs879470657
• NM_018125.4:c.580G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018125.4(ARHGEF10L):​c.580G>C​(p.Ala194Pro) 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. 17/22 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. A194T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARHGEF10L NM_018125.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0570
• Publications: 0 publications found

Genes affected

ARHGEF10L (HGNC:25540): (Rho guanine nucleotide exchange factor 10 like) This gene belongs to the RhoGEF subfamily of RhoGTPases. Members of this subfamily are activated by specific guanine nucleotide exchange factors (GEFs) and are involved in signal transduction. The encoded protein shows cytosolic distribution. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13107592).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018125.4. 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
	ARHGEF10L	NM_018125.4	MANE Select	c.580G>C	p.Ala194Pro	missense	Exon 7 of 29	NP_060595.3
	ARHGEF10L	NM_001011722.2		c.580G>C	p.Ala194Pro	missense	Exon 6 of 27	NP_001011722.2	Q9HCE6-2
	ARHGEF10L	NM_001438939.1		c.583G>C	p.Ala195Pro	missense	Exon 7 of 27	NP_001425868.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF10L	ENST00000361221.8	TSL:1 MANE Select	c.580G>C	p.Ala194Pro	missense	Exon 7 of 29	ENSP00000355060.3	Q9HCE6-1
	ARHGEF10L	ENST00000375415.5	TSL:1	c.580G>C	p.Ala194Pro	missense	Exon 6 of 27	ENSP00000364564.1	Q9HCE6-2
	ARHGEF10L	ENST00000970707.1		c.583G>C	p.Ala195Pro	missense	Exon 7 of 29	ENSP00000640766.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1291090 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 633120

African (AFR) AF: 0.00 AC: 0 AN: 26362

American (AMR) AF: 0.00 AC: 0 AN: 24644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19280

East Asian (EAS) AF: 0.00 AC: 0 AN: 28712

South Asian (SAS) AF: 0.00 AC: 0 AN: 70106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44052

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5050

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1021100

Other (OTH) AF: 0.00 AC: 0 AN: 51784

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.91
DANN	Benign	0.73
DEOGEN2	Benign	0.018	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.057
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.14
Sift	Benign	0.079	T
Sift4G	Benign	0.18	T
Polyphen		0.92	P
Vest4		0.39
MutPred		0.12		Gain of catalytic residue at P193 (P = 0.0133)
MVP		0.072
MPC		0.15
ClinPred		0.061	T
GERP RS		-6.8
Varity_R		0.048
gMVP		0.18
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs879470657; hg19: chr1-17934443;