Genetic Variant MCF2:c.1543+91G>T (chrX-139614790-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001171876.2(MCF2):c.1543+91G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000238 in 841,954 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.0000014 ( 0 hom. 0 hem. )

Consequence

MCF2
NM_001171876.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0970

Publications

0 publications found

Variant links:

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]

MCF2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.0).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCF2	NM_001171876.2 link	c.1543+91G>T		intron_variant	Intron 13 of 28	ENST00000519895.6	NP_001165347.1	P10911-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCF2	ENST00000519895.6 link	c.1543+91G>T		intron_variant	Intron 13 of 28	2	NM_001171876.2	ENSP00000430276.1		P10911-5

Frequencies

GnomAD3 genomes

AF:

0.00000902

AC:

AN:

110861

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000285

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

AF:

0.00000137

AC:

AN:

731041

Hom.:

AF XY:

0.00

AC XY:

AN XY:

192769

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

17841

American (AMR)

AF:

0.00

AC:

AN:

23260

Ashkenazi Jewish (ASJ)

AF:

0.0000733

AC:

AN:

13640

East Asian (EAS)

AF:

0.00

AC:

AN:

27999

South Asian (SAS)

AF:

0.00

AC:

AN:

37266

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37799

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2849

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

537240

Other (OTH)

AF:

0.00

AC:

AN:

33147

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000902

AC:

AN:

110913

Hom.:

Cov.:

AF XY:

0.0000301

AC XY:

AN XY:

33267

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30643

American (AMR)

AF:

0.00

AC:

AN:

10355

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2630

East Asian (EAS)

AF:

0.000286

AC:

AN:

3498

South Asian (SAS)

AF:

0.00

AC:

AN:

2632

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5902

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52831

Other (OTH)

AF:

0.00

AC:

AN:

1521

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.49

(source)

DANN

Benign

0.36

PhyloP100

0.097

PromoterAI

-0.00010

Neutral

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over