rs149949971

chr15-66781228-A-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BS1_Supporting BS2

The NM_005585.5(SMAD6):c.1184A>G(p.Lys395Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000109 in 1,608,868 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00060 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000058 (0 hom.)
• Consequence: SMAD6 NM_005585.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.27

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 Benign. Variant got -7 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.023826927).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000604 (92/152348) while in subpopulation AFR AF= 0.00197 (82/41582). AF 95% confidence interval is 0.00163. There are 1 homozygotes in gnomad4. There are 44 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 92 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD6	NM_005585.5	c.1184A>G	p.Lys395Arg	missense_variant	4/4	ENST00000288840.10
SMAD6	XM_011521561.3	c.401A>G	p.Lys134Arg	missense_variant	4/4
SMAD6	NR_027654.2	n.2339A>G		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD6	ENST00000288840.10	c.1184A>G	p.Lys395Arg	missense_variant	4/4	1	NM_005585.5	P1
SMAD6	ENST00000557916.5	c.*299A>G		3_prime_UTR_variant, NMD_transcript_variant	5/5	1
SMAD6	ENST00000559931.5	c.*299A>G		3_prime_UTR_variant, NMD_transcript_variant	4/4	3

Frequencies

GnomAD3 genomes AF: 0.000604 AC: 92 AN: 152230 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

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: 0.00

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000125 AC: 30 AN: 240546 Hom.: 0 AF XY: 0.0000910 AC XY: 12 AN XY: 131830

Gnomad AFR exome AF: 0.00163

Gnomad AMR exome AF: 0.0000292

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: 0.0000184

Gnomad OTH exome AF: 0.000336

GnomAD4 exome AF: 0.0000577 AC: 84 AN: 1456520 Hom.: 0 Cov.: 34 AF XY: 0.0000469 AC XY: 34 AN XY: 724894

Gnomad4 AFR exome AF: 0.00152

Gnomad4 AMR exome AF: 0.000112

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: 0.0000162

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000604 AC: 92 AN: 152348 Hom.: 1 Cov.: 32 AF XY: 0.000591 AC XY: 44 AN XY: 74510

Gnomad4 AFR AF: 0.00197

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.0000579 Hom.: 0

Bravo AF: 0.000661

ESP6500AA AF: 0.000910 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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

Dec 25, 2023

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 395 of the SMAD6 protein (p.Lys395Arg). This variant is present in population databases (rs149949971, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SMAD6-related conditions. ClinVar contains an entry for this variant (Variation ID: 471746). 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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	19
Dann	Benign	0.32
DEOGEN2	Uncertain	0.64	D
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.024	T
MetaSVM	Uncertain	-0.087	T
MutationAssessor	Benign	-0.015	N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	0.36	N
REVEL	Uncertain	0.41
Sift	Benign	0.83	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.12
MVP		0.86
MPC		0.21
ClinPred		0.0037	T
GERP RS		4.5
Varity_R		0.13
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: rs149949971; hg19: chr15-67073566;