4-105645380-A-C

Variant summary

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

The NM_001242729.2(ARHGEF38):c.867A>C(p.Lys289Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000292 in 1,371,258 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: ARHGEF38 NM_001242729.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.752

Genes affected

ARHGEF38 (HGNC:25968): (Rho guanine nucleotide exchange factor 38) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of catalytic activity. Predicted to be located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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/exons	MANE	UniProt
ARHGEF38	NM_001242729.2	c.867A>C	p.Lys289Asn	missense_variant	6/14	ENST00000420470.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF38	ENST00000420470.3	c.867A>C	p.Lys289Asn	missense_variant	6/14	5	NM_001242729.2	P1
ARHGEF38	ENST00000508036.2	n.567A>C		non_coding_transcript_exon_variant	3/10	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000292 AC: 4 AN: 1371258 Hom.: 0 Cov.: 30 AF XY: 0.00000296 AC XY: 2 AN XY: 675748

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000305

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: 0.00000279

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 26, 2024

The c.867A>C (p.K289N) alteration is located in exon 6 (coding exon 6) of the ARHGEF38 gene. This alteration results from a A to C substitution at nucleotide position 867, causing the lysine (K) at amino acid position 289 to be replaced by an asparagine (N). 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	Pathogenic	0.97
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Benign	0.053
Eigen_PC	Benign	0.035
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Pathogenic	2.9	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.19
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.66
MutPred		0.62		Gain of ubiquitination at K294 (P = 0.0544);
MVP		0.19
MPC		0.32
ClinPred		0.99	D
GERP RS		0.33
Varity_R		0.56
gMVP		0.54

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-106566537;