X-139589842-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001171876.2(MCF2):c.2591T>C(p.Ile864Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00192 in 1,188,806 control chromosomes in the GnomAD database, including 36 homozygotes. There are 611 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (18 hom., 328 hem., cov: 23)
  • Exomes 𝑓: 0.0011 (18 hom. 283 hem.)
• Consequence: MCF2 NM_001171876.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.39

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007697314).
• BP6: Variant X-139589842-A-G is Benign according to our data. Variant chrX-139589842-A-G is described in ClinVar as [Benign]. Clinvar id is 777845.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0103 (1149/111785) while in subpopulation AFR AF= 0.0345 (1063/30820). AF 95% confidence interval is 0.0328. There are 18 homozygotes in gnomad4. There are 328 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 18 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCF2	NM_001171876.2	c.2591T>C	p.Ile864Thr	missense_variant	24/29	ENST00000519895.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCF2	ENST00000519895.6	c.2591T>C	p.Ile864Thr	missense_variant	24/29	2	NM_001171876.2	P4

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1148 AN: 111733 Hom.: 18 Cov.: 23 AF XY: 0.00967 AC XY: 328 AN XY: 33911

Gnomad AFR AF: 0.0345

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00622

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: 0.000169

Gnomad OTH AF: 0.00797

GnomAD3 exomes AF: 0.00316 AC: 529 AN: 167259 Hom.: 8 AF XY: 0.00187 AC XY: 103 AN XY: 55151

Gnomad AFR exome AF: 0.0349

Gnomad AMR exome AF: 0.00352

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000516

Gnomad OTH exome AF: 0.00246

GnomAD4 exome AF: 0.00105 AC: 1132 AN: 1077021 Hom.: 18 Cov.: 26 AF XY: 0.000816 AC XY: 283 AN XY: 346923

Gnomad4 AFR exome AF: 0.0342

Gnomad4 AMR exome AF: 0.00351

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: 0.0000446

Gnomad4 OTH exome AF: 0.00238

GnomAD4 genome AF: 0.0103 AC: 1149 AN: 111785 Hom.: 18 Cov.: 23 AF XY: 0.00965 AC XY: 328 AN XY: 33973

Gnomad4 AFR AF: 0.0345

Gnomad4 AMR AF: 0.00621

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000169

Gnomad4 OTH AF: 0.00787

Alfa AF: 0.00116 Hom.: 28

Bravo AF: 0.0116

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0305 AC: 117

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.00333 AC: 404

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	23
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0077	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.68	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.47	T
REVEL	Benign	0.13
Polyphen		0.84, 0.76, 0.99	.;P;.;.;.;.;P;D
Vest4		0.24, 0.25, 0.22, 0.23, 0.21, 0.24
MVP		0.37
MPC		0.40
ClinPred		0.052	T
GERP RS		4.8
Varity_R		0.58
gMVP		0.48

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

LitVar

Other links and lift over

dbSNP: rs73634052; hg19: chrX-138672001;