rs4875

chr3-158602808-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001369783.1(MLF1):c.615T>C(p.Ser205=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.537 in 1,610,636 control chromosomes in the GnomAD database, including 235,459 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.58 (25971 hom., cov: 31)
  • Exomes 𝑓: 0.53 (209488 hom.)
• Consequence: MLF1 NM_001369783.1 splice_region, synonymous
• Scores: Splicing: ADA: 0.004298
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.57

Genes affected

MLF1 (HGNC:7125): (myeloid leukemia factor 1) This gene encodes an oncoprotein which is thought to play a role in the phenotypic determination of hemopoetic cells. Translocations between this gene and nucleophosmin have been associated with myelodysplastic syndrome and acute myeloid leukemia. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2010]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 3-158602808-T-C is Benign according to our data. Variant chr3-158602808-T-C is described in ClinVar as [Benign]. Clinvar id is 3059532.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-158602808-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.57 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.712 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLF1	NM_001369783.1	c.615T>C	p.Ser205=	splice_region_variant, synonymous_variant	7/8	ENST00000466246.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLF1	ENST00000466246.7	c.615T>C	p.Ser205=	splice_region_variant, synonymous_variant	7/8	2	NM_001369783.1

Frequencies

GnomAD3 genomes AF: 0.576 AC: 87398 AN: 151842 Hom.: 25929 Cov.: 31

Gnomad AFR AF: 0.719

Gnomad AMI AF: 0.480

Gnomad AMR AF: 0.538

Gnomad ASJ AF: 0.507

Gnomad EAS AF: 0.337

Gnomad SAS AF: 0.588

Gnomad FIN AF: 0.530

Gnomad MID AF: 0.595

Gnomad NFE AF: 0.527

Gnomad OTH AF: 0.553

GnomAD3 exomes AF: 0.540 AC: 135143 AN: 250350 Hom.: 37281 AF XY: 0.540 AC XY: 73008 AN XY: 135318

Gnomad AFR exome AF: 0.723

Gnomad AMR exome AF: 0.568

Gnomad ASJ exome AF: 0.518

Gnomad EAS exome AF: 0.324

Gnomad SAS exome AF: 0.592

Gnomad FIN exome AF: 0.515

Gnomad NFE exome AF: 0.533

Gnomad OTH exome AF: 0.528

GnomAD4 exome AF: 0.533 AC: 777426 AN: 1458676 Hom.: 209488 Cov.: 35 AF XY: 0.534 AC XY: 387831 AN XY: 725724

Gnomad4 AFR exome AF: 0.729

Gnomad4 AMR exome AF: 0.565

Gnomad4 ASJ exome AF: 0.517

Gnomad4 EAS exome AF: 0.350

Gnomad4 SAS exome AF: 0.594

Gnomad4 FIN exome AF: 0.514

Gnomad4 NFE exome AF: 0.529

Gnomad4 OTH exome AF: 0.537

GnomAD4 genome AF: 0.576 AC: 87492 AN: 151960 Hom.: 25971 Cov.: 31 AF XY: 0.576 AC XY: 42784 AN XY: 74278

Gnomad4 AFR AF: 0.719

Gnomad4 AMR AF: 0.538

Gnomad4 ASJ AF: 0.507

Gnomad4 EAS AF: 0.337

Gnomad4 SAS AF: 0.587

Gnomad4 FIN AF: 0.530

Gnomad4 NFE AF: 0.527

Gnomad4 OTH AF: 0.556

Alfa AF: 0.534 Hom.: 48564

Bravo AF: 0.582

Asia WGS AF: 0.532 AC: 1851 AN: 3478

EpiCase AF: 0.535

EpiControl AF: 0.540

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

MLF1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	6.8
Dann	Benign	0.41

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0043
dbscSNV1_RF	Benign	0.14
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: rs4875; hg19: chr3-158320597; COSMIC: COSV63034844; COSMIC: COSV63034844;