X-139604909-G-C

Position:

• chrX-139604909-G-C

Variant summary

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

The NM_001171876.2(MCF2):​c.1861C>G​(p.Leu621Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: MCF2 NM_001171876.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.47

Genes affected

MCF2 (HGNC:6940): (MCF.2 cell line derived transforming sequence) The oncogenic protein encoded by this gene is a guanine nucleotide exchange factor (GEF) that exerts control over some members of the Rho family of small GTPases. Several transcript variants encoding different isoforms have been found for this gene. These isoforms exhibit different expression patterns and varying levels of GEF activity.[provided by RefSeq, Jan 2010]

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
MCF2	NM_001171876.2	c.1861C>G	p.Leu621Val	missense_variant	18/29	ENST00000519895.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCF2	ENST00000519895.6	c.1861C>G	p.Leu621Val	missense_variant	18/29	2	NM_001171876.2	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 23

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

Jan 16, 2024

The c.1861C>G (p.L621V) alteration is located in exon 18 (coding exon 17) of the MCF2 gene. This alteration results from a C to G substitution at nucleotide position 1861, causing the leucine (L) at amino acid position 621 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	0.30
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	.;T;.;.;T;.;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.65	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.3	.;M;.;.;.;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.9	.;D;D;D;D;D;D;D
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	.;D;D;D;D;D;D;D
Sift4G	Benign	0.10	.;T;T;T;T;T;T;T
Polyphen		1.0, 0.99	.;D;.;.;.;.;D;D
Vest4		0.73, 0.67, 0.78, 0.73, 0.75, 0.73
MVP		0.77
MPC		0.79
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.85
gMVP		0.51

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: chrX-138687068; COSMIC: COSV58491429; COSMIC: COSV58491429;