15-66703277-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_005585.5(SMAD6):c.19T>C(p.Ser7Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S7S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMAD6 NM_005585.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.42

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 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_005585.5
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD6	NM_005585.5	c.19T>C	p.Ser7Pro	missense_variant	1/4	ENST00000288840.10
SMAD6	NR_027654.2	n.1042T>C		non_coding_transcript_exon_variant	1/5
SMAD6	XR_931827.3	n.1042T>C		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD6	ENST00000288840.10	c.19T>C	p.Ser7Pro	missense_variant	1/4	1	NM_005585.5	P1
SMAD6	ENST00000557916.5	c.19T>C	p.Ser7Pro	missense_variant, NMD_transcript_variant	1/5	1
SMAD6	ENST00000612349.1	n.201T>C		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1331952 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 658024

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Aug 29, 2021

This sequence change replaces serine with proline at codon 7 of the SMAD6 protein (p.Ser7Pro). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and proline. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with SMAD6-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.87	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.94	N
REVEL	Uncertain	0.50
Sift	Benign	0.12	T
Sift4G	Uncertain	0.0040	D
Polyphen		0.94	P
Vest4		0.35
MutPred		0.20		Loss of phosphorylation at S7 (P = 0.0046);
MVP		0.77
MPC		2.6
ClinPred		0.91	D
GERP RS		3.9
Varity_R		0.26
gMVP		0.63

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: rs1448375284; hg19: chr15-66995615;