Genetic Variant MELTF:p.Ala737Thr (chr3-197003380-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005929.6(MELTF):c.2209G>A(p.Ala737Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000827 in 1,028,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000072 ( 0 hom. )

Consequence

MELTF
NM_005929.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.31

Variant links:

Genes affected

MELTF (HGNC:7037): (melanotransferrin) The protein encoded by this gene is a cell-surface glycoprotein found on melanoma cells. The protein shares sequence similarity and iron-binding properties with members of the transferrin superfamily. The importance of the iron binding function has not yet been identified. This gene resides in the same region of chromosome 3 as members of the transferrin superfamily. Alternative splicing results in two transcript variants. [provided by RefSeq, Jul 2008]

MELTF links:

MELTF-AS1 (HGNC:40373): (MELTF antisense RNA 1)

MELTF-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.013778061).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MELTF	NM_005929.6 link	c.2209G>A	p.Ala737Thr	missense_variant	Exon 16 of 16	ENST00000296350.10	NP_005920.2	P08582-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MELTF	ENST00000296350.10 link	c.2209G>A	p.Ala737Thr	missense_variant	Exon 16 of 16	1	NM_005929.6	ENSP00000296350.5		P08582-1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

144788

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00561

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000305

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000725

AC:

AN:

883308

Hom.:

Cov.:

AF XY:

0.0000922

AC XY:

AN XY:

412296

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00511

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000214

Gnomad4 OTH exome

AF:

0.000430

GnomAD4 genome

AF:

0.000145

AC:

AN:

144788

Hom.:

Cov.:

AF XY:

0.000128

AC XY:

AN XY:

70408

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00561

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000305

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000253

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 23, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2209G>A (p.A737T) alteration is located in exon 16 (coding exon 16) of the MELTF gene. This alteration results from a G to A substitution at nucleotide position 2209, causing the alanine (A) at amino acid position 737 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.73

CADD

Benign

2.9

DANN

Benign

0.97

DEOGEN2

Benign

0.027

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.29

M_CAP

Benign

0.0065

MetaRNN

Benign

0.014

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.0

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.010

REVEL

Benign

0.0060

Sift

Pathogenic

0.0

Sift4G

Benign

0.60

Polyphen

0.043

Vest4

0.061

MutPred

0.18

Loss of glycosylation at P736 (P = 0.0491);

MVP

0.014

MPC

0.20

ClinPred

0.11

GERP RS

-4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.5

Varity_R

0.089

gMVP

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over