X-139582456-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PVS1_Moderate BP6_Moderate BS1 BS2

The ENST00000370573.8(MCF2):c.2570C>G(p.Ser857Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,207,273 control chromosomes in the GnomAD database, including 37 homozygotes. There are 631 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 (19 hom., 323 hem., cov: 23)
  • Exomes 𝑓: 0.0011 (18 hom. 308 hem.)
• Consequence: MCF2 ENST00000370573.8 stop_gained
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.225

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 -8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00503 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BP6: Variant X-139582456-G-C is Benign according to our data. Variant chrX-139582456-G-C is described in ClinVar as [Benign]. Clinvar id is 777844.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0102 (1147/111964) while in subpopulation AFR AF= 0.0345 (1065/30837). AF 95% confidence interval is 0.0328. There are 19 homozygotes in gnomad4. There are 323 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 19 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCF2	NM_001171876.2	c.*15C>G		3_prime_UTR_variant	29/29	ENST00000519895.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCF2	ENST00000519895.6	c.*15C>G		3_prime_UTR_variant	29/29	2	NM_001171876.2	P4

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1146 AN: 111910 Hom.: 19 Cov.: 23 AF XY: 0.00948 AC XY: 323 AN XY: 34086

Gnomad AFR AF: 0.0346

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00579

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: 0.00312 AC: 567 AN: 181747 Hom.: 9 AF XY: 0.00207 AC XY: 138 AN XY: 66695

Gnomad AFR exome AF: 0.0356

Gnomad AMR exome AF: 0.00323

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: 0.0000495

Gnomad OTH exome AF: 0.00224

GnomAD4 exome AF: 0.00108 AC: 1180 AN: 1095309 Hom.: 18 Cov.: 28 AF XY: 0.000853 AC XY: 308 AN XY: 360983

Gnomad4 AFR exome AF: 0.0346

Gnomad4 AMR exome AF: 0.00333

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: 0.0000453

Gnomad4 OTH exome AF: 0.00239

GnomAD4 genome AF: 0.0102 AC: 1147 AN: 111964 Hom.: 19 Cov.: 23 AF XY: 0.00946 AC XY: 323 AN XY: 34150

Gnomad4 AFR AF: 0.0345

Gnomad4 AMR AF: 0.00579

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: 0.00175 Hom.: 33

Bravo AF: 0.0116

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0300 AC: 115

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.00327 AC: 397

EpiCase AF: 0.00

EpiControl AF: 0.0000595

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
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	7.9
Dann	Uncertain	0.99
FATHMM_MKL	Benign	0.029	N
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
Vest4		0.19
GERP RS		0.58

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: rs73634050; hg19: chrX-138664615;