X-139598414-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001171876.2(MCF2):c.2149T>G(p.Leu717Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 112,336 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 23)
• Consequence: MCF2 NM_001171876.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.50

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.818

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCF2	NM_001171876.2	c.2149T>G	p.Leu717Val	missense_variant	21/29	ENST00000519895.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCF2	ENST00000519895.6	c.2149T>G	p.Leu717Val	missense_variant	21/29	2	NM_001171876.2	P4

Frequencies

GnomAD3 genomes AF: 0.00000890 AC: 1 AN: 112336 Hom.: 0 Cov.: 23 AF XY: 0.0000290 AC XY: 1 AN XY: 34540

Gnomad AFR AF: 0.0000323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 19

GnomAD4 genome AF: 0.00000890 AC: 1 AN: 112336 Hom.: 0 Cov.: 23 AF XY: 0.0000290 AC XY: 1 AN XY: 34540

Gnomad4 AFR AF: 0.0000323

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

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

Nov 18, 2022

The c.2149T>G (p.L717V) alteration is located in exon 21 (coding exon 20) of the MCF2 gene. This alteration results from a T to G substitution at nucleotide position 2149, causing the leucine (L) at amino acid position 717 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	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Benign	23
Dann	Uncertain	0.99
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.36	D
MutationTaster	Benign	0.83	N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.74	T
REVEL	Uncertain	0.64
Polyphen		1.0, 1.0	.;D;.;.;.;.;D;D
Vest4		0.71, 0.67, 0.70, 0.68, 0.71, 0.70
MVP		0.99
MPC		0.51
ClinPred		1.0	D
GERP RS		1.5
Varity_R		0.76
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2049185935; hg19: chrX-138680573;