15-66781042-G-C

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1BP4_ModerateBS1_SupportingBS2

The NM_005585.5(SMAD6):c.998G>C(p.Ser333Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000196 in 1,600,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

SMAD6
NM_005585.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 4.44

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.

PM1

In a domain MH2 (size 165) in uniprot entity SMAD6_HUMAN there are 9 pathogenic changes around while only 3 benign (75%) in NM_005585.5

BP4

Computational evidence support a benign effect (MetaRNN=0.08331406).

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000198 (287/1448226) while in subpopulation NFE AF= 0.000246 (273/1109828). AF 95% confidence interval is 0.000222. There are 0 homozygotes in gnomad4_exome. There are 125 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD6	NM_005585.5 link	c.998G>C	p.Ser333Thr	missense_variant	Exon 4 of 4	ENST00000288840.10	NP_005576.3	O43541-1
SMAD6	XM_011521561.3 link	c.215G>C	p.Ser72Thr	missense_variant	Exon 4 of 4		XP_011519863.1	O43541-2
SMAD6	NR_027654.2 link	n.2153G>C		non_coding_transcript_exon_variant	Exon 5 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD6	ENST00000288840.10 link	c.998G>C	p.Ser333Thr	missense_variant	Exon 4 of 4	1	NM_005585.5	ENSP00000288840.5		O43541-1

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000104

AC:

AN:

229762

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

126044

show subpopulations

Gnomad AFR exome

AF:

0.0000690

Gnomad AMR exome

AF:

0.0000296

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:

0.000209

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000198

AC:

287

AN:

1448226

Hom.:

Cov.:

AF XY:

0.000174

AC XY:

125

AN XY:

720434

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000113

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000246

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.000177

AC:

AN:

152362

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000248

Hom.:

Bravo

AF:

0.000238

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000909

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Aortic valve disease 2

Uncertain:1

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 333 of the SMAD6 protein (p.Ser333Thr). This variant is present in population databases (rs199531653, 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: 471766). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SMAD6 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect SMAD6 function (PMID: 32499606). 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. -

not provided

Uncertain:1

Mar 30, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Identified in a patient with craniosynostosis in published literature; however, the variant did not appear to negatively affect SMAD6 inhibitory function on luciferase assay (Calpena et al., 2020); This variant is associated with the following publications: (PMID: 32499606) -

not specified

Benign:1

Mar 31, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SMAD6 c.998G>C (p.Ser333Thr) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 229762 control chromosomes. The observed variant frequency is approximately 3.34 fold of the estimated maximal expected allele frequency for a pathogenic variant in SMAD6 causing Aortic Valve Disease phenotype (3.1e-05). c.998G>C has been reported in the literature in individuals affected with Aortic Valve Disease. These report(s) do not provide unequivocal conclusions about association of the variant with Aortic Valve Disease. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. ClinVar contains an entry for this variant (Variation ID: 471766). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.037

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

DANN

Benign

0.91

DEOGEN2

Uncertain

0.68

Eigen

Benign

0.017

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.76

M_CAP

Uncertain

0.090

MetaRNN

Benign

0.083

MetaSVM

Uncertain

0.55

MutationAssessor

Benign

1.3

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.83

REVEL

Uncertain

0.40

Sift

Benign

0.37

Sift4G

Benign

0.64

Polyphen

0.014

Vest4

0.29

MVP

0.79

MPC

0.27

ClinPred

0.041

GERP RS

4.6

Varity_R

0.22

gMVP

0.30

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over