NM_005585.5:c.1405G>A

Variant names:

• chr15-66781449-G-A
• rs1416212959
• NM_005585.5:c.1405G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005585.5(SMAD6):​c.1405G>A​(p.Ala469Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,452,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. A469P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SMAD6 NM_005585.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.87
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• craniosynostosis 7

  Inheritance: AD, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• radioulnar synostosis, nonsyndromic, susceptibility to

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• aortic valve disease 2

  Inheritance: AD, Unknown Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• familial bicuspid aortic valve

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital radioulnar synostosis

  Inheritance: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet
• congenital heart defects, multiple types

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD6	NM_005585.5	c.1405G>A	p.Ala469Thr	missense_variant	Exon 4 of 4	ENST00000288840.10	NP_005576.3
SMAD6	XM_011521561.3	c.622G>A	p.Ala208Thr	missense_variant	Exon 4 of 4		XP_011519863.1
SMAD6	NR_027654.2	n.2560G>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.1405G>A	p.Ala469Thr	missense_variant	Exon 4 of 4	1	NM_005585.5	ENSP00000288840.5
SMAD6	ENST00000557916.5	n.*520G>A		downstream_gene_variant		1		ENSP00000452955.1
SMAD6	ENST00000559931.5	n.*520G>A		downstream_gene_variant		3		ENSP00000453446.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1452760 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 722842

African (AFR) AF: 0.00 AC: 0 AN: 33296

American (AMR) AF: 0.00 AC: 0 AN: 44518

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26004

East Asian (EAS) AF: 0.00 AC: 0 AN: 39548

South Asian (SAS) AF: 0.00 AC: 0 AN: 86102

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110068

Other (OTH) AF: 0.00 AC: 0 AN: 60116

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000314 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Feb 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A469T variant (also known as c.1405G>A), located in coding exon 4 of the SMAD6 gene, results from a G to A substitution at nucleotide position 1405. The alanine at codon 469 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.71		Loss of catalytic residue at A469 (P = 0.0968);
MVP		0.94
MPC		0.89
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.58
gMVP		0.55
Mutation Taster		=40/60	disease causing

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

Other links and lift over

dbSNP: rs1416212959; hg19: chr15-67073787;