rs1056072996

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_005585.5(SMAD6):c.253C>T(p.Arg85Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000875 in 1,223,168 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000084 ( 1 hom. )

Consequence

SMAD6
NM_005585.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0510

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 Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3240858).

BS2

High AC in GnomAd at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SMAD6	NM_005585.5 linkuse as main transcript	c.253C>T	p.Arg85Cys	missense_variant	1/4	ENST00000288840.10
SMAD6	NR_027654.2 linkuse as main transcript	n.1276C>T		non_coding_transcript_exon_variant	1/5
SMAD6	XR_931827.3 linkuse as main transcript	n.1276C>T		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD6	ENST00000288840.10 linkuse as main transcript	c.253C>T	p.Arg85Cys	missense_variant	1/4	1	NM_005585.5	P1	O43541-1
SMAD6	ENST00000557916.5 linkuse as main transcript	c.253C>T	p.Arg85Cys	missense_variant, NMD_transcript_variant	1/5	1			O43541-4
SMAD6	ENST00000612349.1 linkuse as main transcript	n.435C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

151234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000969

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000177

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000840

AC:

AN:

1071934

Hom.:

Cov.:

AF XY:

0.0000927

AC XY:

AN XY:

507134

show subpopulations

Gnomad4 AFR exome

AF:

0.0000452

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000747

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000943

Gnomad4 OTH exome

AF:

0.0000472

GnomAD4 genome

AF:

0.000112

AC:

AN:

151234

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

73838

show subpopulations

Gnomad4 AFR

AF:

0.0000969

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000289

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000177

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000285

Hom.:

Bravo

AF:

0.000136

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Aortic valve disease 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 85 of the SMAD6 protein (p.Arg85Cys). This variant is present in population databases (no rsID available, gnomAD 0.02%). This missense change has been observed in individual(s) with craniosynostosis (PMID: 32499606). ClinVar contains an entry for this variant (Variation ID: 471755). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.030

BayesDel_noAF

Benign

-0.28

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Benign

0.31

Eigen

Benign

-0.018

Eigen_PC

Benign

-0.026

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.71

M_CAP

Pathogenic

0.80

MetaRNN

Benign

0.32

MetaSVM

Benign

-0.79

MutationAssessor

Benign

1.1

MutationTaster

Benign

0.99

D;D

PrimateAI

Pathogenic

0.97

PROVEAN

Benign

-0.48

REVEL

Benign

0.24

Sift

Benign

0.084

Sift4G

Benign

0.078

Polyphen

1.0

Vest4

0.25

MutPred

0.36

Loss of methylation at R85 (P = 0.0157);

MVP

0.82

MPC

2.0

ClinPred

0.57

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.10

gMVP

0.47

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