rs3934907

Variant names:

• chr15-66769097-C-A
• rs3934907
• NM_005585.5:c.953-11900C>A

Variant summary

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

The NM_005585.5(SMAD6):​c.953-11900C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.208 in 152,082 control chromosomes in the GnomAD database, including 4,185 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 0.21 (4185 hom., cov: 32)
• Consequence: SMAD6 NM_005585.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.74
• Publications: 7 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.364 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD6	NM_005585.5	c.953-11900C>A		intron_variant	Intron 3 of 3	ENST00000288840.10	NP_005576.3
SMAD6	NR_027654.2	n.2108-11900C>A		intron_variant	Intron 4 of 4
SMAD6	XM_011521561.3	c.170-11900C>A		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.953-11900C>A		intron_variant	Intron 3 of 3	1	NM_005585.5	ENSP00000288840.5
SMAD6	ENST00000557916.5	n.*68-11900C>A		intron_variant	Intron 4 of 4	1		ENSP00000452955.1
SMAD6	ENST00000559931.5	n.*68-11900C>A		intron_variant	Intron 3 of 3	3		ENSP00000453446.1

Frequencies

GnomAD3 genomes AF: 0.208 AC: 31614 AN: 151964 Hom.: 4169 Cov.: 32

Gnomad AFR AF: 0.369

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.159

Gnomad EAS AF: 0.299

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.131

Gnomad OTH AF: 0.181

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

GnomAD4 genome AF: 0.208 AC: 31682 AN: 152082 Hom.: 4185 Cov.: 32 AF XY: 0.208 AC XY: 15447 AN XY: 74364

African (AFR) AF: 0.369 AC: 15290 AN: 41426

American (AMR) AF: 0.165 AC: 2518 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 552 AN: 3472

East Asian (EAS) AF: 0.300 AC: 1552 AN: 5170

South Asian (SAS) AF: 0.212 AC: 1024 AN: 4824

European-Finnish (FIN) AF: 0.127 AC: 1342 AN: 10596

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.131 AC: 8878 AN: 67992

Other (OTH) AF: 0.185 AC: 390 AN: 2112

Alfa AF: 0.150 Hom.: 3362

Bravo AF: 0.217

Asia WGS AF: 0.317 AC: 1099 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.059
DANN	Benign	0.39
PhyloP100		-2.7
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: rs3934907; hg19: chr15-67061435;