rs11858577

Variant names:

• chr15-66774225-C-T
• rs11858577
• NM_005585.5:c.953-6772C>T

Variant summary

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

The NM_005585.5(SMAD6):​c.953-6772C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 152,194 control chromosomes in the GnomAD database, including 942 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 0.10 (942 hom., cov: 32)
• Consequence: SMAD6 NM_005585.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.246
• Publications: 12 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=-0.58).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD6	NM_005585.5	c.953-6772C>T		intron_variant	Intron 3 of 3	ENST00000288840.10	NP_005576.3
SMAD6	NR_027654.2	n.2108-6772C>T		intron_variant	Intron 4 of 4
SMAD6	XM_011521561.3	c.170-6772C>T		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.953-6772C>T		intron_variant	Intron 3 of 3	1	NM_005585.5	ENSP00000288840.5
SMAD6	ENST00000557916.5	n.*68-6772C>T		intron_variant	Intron 4 of 4	1		ENSP00000452955.1
SMAD6	ENST00000559931.5	n.*68-6772C>T		intron_variant	Intron 3 of 3	3		ENSP00000453446.1

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15576 AN: 152076 Hom.: 941 Cov.: 32

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.0600

Gnomad ASJ AF: 0.0798

Gnomad EAS AF: 0.0661

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.0949

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0804

Gnomad OTH AF: 0.0905

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

GnomAD4 genome AF: 0.102 AC: 15592 AN: 152194 Hom.: 942 Cov.: 32 AF XY: 0.103 AC XY: 7678 AN XY: 74398

African (AFR) AF: 0.162 AC: 6709 AN: 41502

American (AMR) AF: 0.0599 AC: 917 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0798 AC: 277 AN: 3470

East Asian (EAS) AF: 0.0662 AC: 343 AN: 5178

South Asian (SAS) AF: 0.118 AC: 568 AN: 4828

European-Finnish (FIN) AF: 0.0949 AC: 1007 AN: 10608

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0804 AC: 5469 AN: 67988

Other (OTH) AF: 0.0910 AC: 192 AN: 2110

Alfa AF: 0.0837 Hom.: 2476

Bravo AF: 0.102

Asia WGS AF: 0.0870 AC: 302 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	11
DANN	Benign	0.95
PhyloP100		-0.25
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: rs11858577; hg19: chr15-67066563;