NM_005585.5:c.973G>A

Variant names:

• chr15-66781017-G-A
• rs199822239
• NM_005585.5:c.973G>A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_005585.5(SMAD6):​c.973G>A​(p.Ala325Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000231 in 1,580,110 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 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (1 hom.)
• Consequence: SMAD6 NM_005585.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 5.77

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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08999571).
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.00024 (343/1427934) while in subpopulation AFR AF= 0.000367 (12/32738). AF 95% confidence interval is 0.000255. There are 1 homozygotes in gnomad4_exome. There are 166 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 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD6	NM_005585.5	c.973G>A	p.Ala325Thr	missense_variant	Exon 4 of 4	ENST00000288840.10	NP_005576.3
SMAD6	XM_011521561.3	c.190G>A	p.Ala64Thr	missense_variant	Exon 4 of 4		XP_011519863.1
SMAD6	NR_027654.2	n.2128G>A		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	c.973G>A	p.Ala325Thr	missense_variant	Exon 4 of 4	1	NM_005585.5	ENSP00000288840.5

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000131 AC: 27 AN: 205972 Hom.: 0 AF XY: 0.000132 AC XY: 15 AN XY: 113636

Gnomad AFR exome AF: 0.0000806

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000213

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000257

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000240 AC: 343 AN: 1427934 Hom.: 1 Cov.: 34 AF XY: 0.000234 AC XY: 166 AN XY: 708366

Gnomad4 AFR exome AF: 0.000367

Gnomad4 AMR exome AF: 0.0000468

Gnomad4 ASJ exome AF: 0.000155

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000281

Gnomad4 OTH exome AF: 0.000253

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74332

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000365 Hom.: 0

Bravo AF: 0.000181

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000149 AC: 18

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

SMAD6-related disorder Uncertain:1

Sep 24, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SMAD6 c.973G>A variant is predicted to result in the amino acid substitution p.Ala325Thr. This variant was reported in an individual with congenital mitral regurgitation (Tan et al. 2012. PubMed ID: 22275001). Functional studies showed that this variant does not significantly affect protein function (Tan et al. 2012. PubMed ID: 22275001; Calpena et al. 2020. PubMed ID: 32499606). This variant is reported in 0.027% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-67073355-G-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Aortic valve disease 2 Uncertain:1

Oct 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 325 of the SMAD6 protein (p.Ala325Thr). This variant is present in population databases (rs199822239, gnomAD 0.03%). This missense change has been observed in individual(s) with congenital cardiovascular malformation (PMID: 22275001). ClinVar contains an entry for this variant (Variation ID: 405517). 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: 22275001, 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

Sep 02, 2023

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; Observed in an individual with congenital mitral regurgitation (Tan et al., 2012); This variant is associated with the following publications: (PMID: 32499606, 22275001) -

Craniosynostosis 7 Uncertain:1

Nov 30, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: BP4 supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Uncertain	0.0
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.083
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.090	T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	1.3	L
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.74	N
REVEL	Uncertain	0.37
Sift	Benign	0.25	T
Sift4G	Benign	0.29	T
Polyphen		0.011	B
Vest4		0.11
MVP		0.82
MPC		0.25
ClinPred		0.082	T
GERP RS		4.6
Varity_R		0.083
gMVP		0.37

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: rs199822239; hg19: chr15-67073355; COSMIC: COSV56595702;