15-66761735-A-G

Variant names:

• chr15-66761735-A-G
• rs7180265
• NM_005585.5:c.953-19262A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005585.5(SMAD6):​c.953-19262A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.679 in 152,008 control chromosomes in the GnomAD database, including 35,170 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.68 (35170 hom., cov: 31)
• Consequence: SMAD6 NM_005585.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.224
• Publications: 2 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.888 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD6	NM_005585.5	c.953-19262A>G		intron_variant	Intron 3 of 3	ENST00000288840.10	NP_005576.3
SMAD6	NR_027654.2	n.2108-19262A>G		intron_variant	Intron 4 of 4
SMAD6	XM_011521561.3	c.170-19262A>G		intron_variant	Intron 3 of 3		XP_011519863.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD6	ENST00000288840.10	c.953-19262A>G		intron_variant	Intron 3 of 3	1	NM_005585.5	ENSP00000288840.5
SMAD6	ENST00000557916.5	n.*68-19262A>G		intron_variant	Intron 4 of 4	1		ENSP00000452955.1
SMAD6	ENST00000559931.5	n.*68-19262A>G		intron_variant	Intron 3 of 3	3		ENSP00000453446.1

Frequencies

GnomAD3 genomes AF: 0.679 AC: 103131 AN: 151890 Hom.: 35135 Cov.: 31

Gnomad AFR AF: 0.643

Gnomad AMI AF: 0.700

Gnomad AMR AF: 0.742

Gnomad ASJ AF: 0.680

Gnomad EAS AF: 0.910

Gnomad SAS AF: 0.742

Gnomad FIN AF: 0.697

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.661

Gnomad OTH AF: 0.683

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.679 AC: 103218 AN: 152008 Hom.: 35170 Cov.: 31 AF XY: 0.684 AC XY: 50777 AN XY: 74284

African (AFR) AF: 0.643 AC: 26624 AN: 41408

American (AMR) AF: 0.743 AC: 11359 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.680 AC: 2359 AN: 3470

East Asian (EAS) AF: 0.910 AC: 4691 AN: 5154

South Asian (SAS) AF: 0.742 AC: 3571 AN: 4812

European-Finnish (FIN) AF: 0.697 AC: 7378 AN: 10580

Middle Eastern (MID) AF: 0.651 AC: 190 AN: 292

European-Non Finnish (NFE) AF: 0.661 AC: 44961 AN: 67974

Other (OTH) AF: 0.684 AC: 1447 AN: 2116

Alfa AF: 0.676 Hom.: 15371

Bravo AF: 0.683

Asia WGS AF: 0.797 AC: 2766 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.3
DANN	Benign	0.73
PhyloP100		-0.22
Mutation Taster		=100/0	polymorphism (auto)

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: rs7180265; hg19: chr15-67054073;