rs199531653

chr15-66781042-G-Achr15-66781042-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_005585.5(SMAD6):c.998G>A(p.Ser333Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000207 in 1,448,228 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S333T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SMAD6 NM_005585.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.44

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]

ACMG classification

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 NM_005585.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20842084).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD6	NM_005585.5	c.998G>A	p.Ser333Asn	missense_variant	4/4	ENST00000288840.10
SMAD6	XM_011521561.3	c.215G>A	p.Ser72Asn	missense_variant	4/4
SMAD6	NR_027654.2	n.2153G>A		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD6	ENST00000288840.10	c.998G>A	p.Ser333Asn	missense_variant	4/4	1	NM_005585.5	P1
SMAD6	ENST00000557916.5	c.*113G>A		3_prime_UTR_variant, NMD_transcript_variant	5/5	1
SMAD6	ENST00000559931.5	c.*113G>A		3_prime_UTR_variant, NMD_transcript_variant	4/4	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000131 AC: 3 AN: 229762 Hom.: 0 AF XY: 0.0000159 AC XY: 2 AN XY: 126044

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000889

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1448228 Hom.: 0 Cov.: 34 AF XY: 0.00000278 AC XY: 2 AN XY: 720434

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000677

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Aortic valve disease 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 10, 2023

This variant has not been reported in the literature in individuals affected with SMAD6-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SMAD6 protein function. 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. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 333 of the SMAD6 protein (p.Ser333Asn). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	21
Dann	Benign	0.97
DEOGEN2	Uncertain	0.73	D
Eigen	Benign	-0.15
Eigen_PC	Benign	0.067
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.21	T
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.070	N
REVEL	Uncertain	0.37
Sift	Benign	0.70	T
Sift4G	Benign	0.73	T
Polyphen		0.0010	B
Vest4		0.13
MutPred		0.65		Gain of catalytic residue at S333 (P = 0.0168);
MVP		0.75
MPC		0.24
ClinPred		0.13	T
GERP RS		4.6
Varity_R		0.20
gMVP		0.33

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

Other links and lift over

dbSNP: rs199531653; hg19: chr15-67073380;