Variant chr15-66781403-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The ENST00000288840.10(SMAD6):c.1359C>A(p.Asp453Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,450,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D453D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SMAD6
ENST00000288840.10 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.389

Variant links:

Genes affected

SMAD6 (HGNC:6772): (SMAD family member 6) The protein encoded by this gene belongs to the SMAD family of proteins, which are related to Drosophila 'mothers against decapentaplegic' (Mad) and C. elegans Sma. SMAD proteins are signal transducers and transcriptional modulators that mediate multiple signaling pathways. This protein functions in the negative regulation of BMP and TGF-beta/activin-signalling. Multiple transcript variants have been found for this gene.[provided by RefSeq, Sep 2014]

SMAD6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a domain MH2 (size 165) in uniprot entity SMAD6_HUMAN there are 15 pathogenic changes around while only 6 benign (71%) in ENST00000288840.10

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0857276).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SMAD6	NM_005585.5 linkuse as main transcript	c.1359C>A	p.Asp453Glu	missense_variant	4/4	ENST00000288840.10	NP_005576.3
SMAD6	XM_011521561.3 linkuse as main transcript	c.576C>A	p.Asp192Glu	missense_variant	4/4		XP_011519863.1
SMAD6	NR_027654.2 linkuse as main transcript	n.2514C>A		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD6	ENST00000288840.10 linkuse as main transcript	c.1359C>A	p.Asp453Glu	missense_variant	4/4	1	NM_005585.5	ENSP00000288840	P1	O43541-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000441

AC:

AN:

226758

Hom.:

AF XY:

0.00000793

AC XY:

AN XY:

126106

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000994

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1450836

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

721964

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

9.01e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000296

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.096

BayesDel_noAF

Benign

-0.38

CADD

Benign

0.25

DANN

Benign

0.40

DEOGEN2

Uncertain

0.63

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.46

M_CAP

Uncertain

0.086

MetaRNN

Benign

0.086

MetaSVM

Uncertain

-0.20

MutationAssessor

Benign

-0.55

MutationTaster

Benign

0.96

D;D

PrimateAI

Uncertain

0.56

PROVEAN

Benign

0.49

REVEL

Uncertain

0.30

Sift

Benign

1.0

Sift4G

Benign

0.94

Polyphen

0.0

Vest4

0.077

MutPred

0.37

Gain of glycosylation at P452 (P = 0.0941);

MVP

0.43

MPC

0.24

ClinPred

0.020

GERP RS

-3.2

Varity_R

0.080

gMVP

0.20

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

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over