1-3463380-C-T

Variant names:

• chr1-3463380-C-T
• rs1639453206
• NM_014448.4:c.296C>T

Variant summary

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

The NM_014448.4(ARHGEF16):​c.296C>T​(p.Ala99Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ARHGEF16 NM_014448.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.67

Genes affected

ARHGEF16 (HGNC:15515): (Rho guanine nucleotide exchange factor 16) Although the specific function of this protein is not known yet, it is thought to be involved in protein-protein and protein-lipid interactions. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF16	NM_014448.4	c.296C>T	p.Ala99Val	missense_variant	Exon 2 of 15	ENST00000378378.9	NP_055263.2
ARHGEF16	XM_017001049.2	c.347C>T	p.Ala116Val	missense_variant	Exon 2 of 15		XP_016856538.1
ARHGEF16	XM_017001051.2	c.296C>T	p.Ala99Val	missense_variant	Exon 2 of 15		XP_016856540.1
ARHGEF16	XM_047418009.1	c.347C>T	p.Ala116Val	missense_variant	Exon 2 of 8		XP_047273965.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF16	ENST00000378378.9	c.296C>T	p.Ala99Val	missense_variant	Exon 2 of 15	2	NM_014448.4	ENSP00000367629.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 08, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.296C>T (p.A99V) alteration is located in exon 2 (coding exon 1) of the ARHGEF16 gene. This alteration results from a C to T substitution at nucleotide position 296, causing the alanine (A) at amino acid position 99 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.27
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.071
Sift	Benign	0.52	T
Sift4G	Benign	1.0	T
Polyphen		0.0060	B
Vest4		0.018
MutPred		0.18		Gain of methylation at K100 (P = 0.0416);
MVP		0.24
MPC		0.26
ClinPred		0.78	D
GERP RS		3.6
Varity_R		0.084
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.39		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1639453206; hg19: chr1-3379944;