rs4875

Variant names:

• chr3-158602808-T-C
• rs4875
• NM_001369783.1:c.615T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_001369783.1(MLF1):​c.615T>C​(p.Ser205Ser) 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 (no stars).

• 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 no assertion criteria provided B:1
• Conservation: PhyloP100: 1.57
• Publications: 37 publications found

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

Our verdict: Benign. The variant received -14 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 no_assertion_criteria_provided, 0 stars.
• 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 rank	MANE	Protein	UniProt
MLF1	NM_001369783.1	c.615T>C	p.Ser205Ser	splice_region_variant, synonymous_variant	Exon 7 of 8	ENST00000466246.7	NP_001356712.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLF1	ENST00000466246.7	c.615T>C	p.Ser205Ser	splice_region_variant, synonymous_variant	Exon 7 of 8	2	NM_001369783.1	ENSP00000417278.2

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

GnomAD2 exomes AF: 0.540 AC: 135143 AN: 250350 AF XY: 0.540

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 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

African (AFR) AF: 0.729 AC: 24359 AN: 33396

American (AMR) AF: 0.565 AC: 25189 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.517 AC: 13488 AN: 26084

East Asian (EAS) AF: 0.350 AC: 13895 AN: 39654

South Asian (SAS) AF: 0.594 AC: 51096 AN: 86038

European-Finnish (FIN) AF: 0.514 AC: 27430 AN: 53374

Middle Eastern (MID) AF: 0.560 AC: 3070 AN: 5478

European-Non Finnish (NFE) AF: 0.529 AC: 586540 AN: 1109808

Other (OTH) AF: 0.537 AC: 32359 AN: 60252

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

African (AFR) AF: 0.719 AC: 29808 AN: 41440

American (AMR) AF: 0.538 AC: 8214 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.507 AC: 1759 AN: 3470

East Asian (EAS) AF: 0.337 AC: 1739 AN: 5164

South Asian (SAS) AF: 0.587 AC: 2820 AN: 4808

European-Finnish (FIN) AF: 0.530 AC: 5591 AN: 10550

Middle Eastern (MID) AF: 0.592 AC: 174 AN: 294

European-Non Finnish (NFE) AF: 0.527 AC: 35774 AN: 67934

Other (OTH) AF: 0.556 AC: 1175 AN: 2114

Alfa AF: 0.546 Hom.: 78942

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: no assertion criteria provided

Submissions by phenotype

MLF1-related disorder Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		1.6
Mutation Taster		=74/26	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4875; hg19: chr3-158320597; COSMIC: COSV63034844; COSMIC: COSV63034844;