rs17264185

Variant names:

• chr15-66704749-A-G
• rs17264185
• NM_005585.5:c.817+674A>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.817+674A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 152,122 control chromosomes in the GnomAD database, including 4,399 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 0.24 (4397 hom., cov: 32)
  • Exomes 𝑓: 0.22 (2 hom.)
• Consequence: SMAD6 NM_005585.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.54
• Publications: 13 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=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.258 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005585.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD6	NM_005585.5	MANE Select	c.817+674A>G		intron	N/A	NP_005576.3
	SMAD6	NR_027654.2		n.1840+674A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD6	ENST00000288840.10	TSL:1 MANE Select	c.817+674A>G		intron	N/A	ENSP00000288840.5
	SMAD6	ENST00000557916.5	TSL:1	n.817+674A>G		intron	N/A	ENSP00000452955.1
	SMAD6	ENST00000612349.1	TSL:6	n.1673A>G		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes AF: 0.239 AC: 36356 AN: 151932 Hom.: 4399 Cov.: 32

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.270

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.237

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.261

Gnomad OTH AF: 0.245

GnomAD4 exome AF: 0.222 AC: 16 AN: 72 Hom.: 2 Cov.: 0 AF XY: 0.241 AC XY: 13 AN XY: 54

African (AFR) AF: 0.500 AC: 1 AN: 2

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.0714 AC: 1 AN: 14

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.304 AC: 14 AN: 46

Other (OTH) AF: 0.00 AC: 0 AN: 6

GnomAD4 genome AF: 0.239 AC: 36360 AN: 152050 Hom.: 4397 Cov.: 32 AF XY: 0.236 AC XY: 17549 AN XY: 74320

African (AFR) AF: 0.231 AC: 9587 AN: 41474

American (AMR) AF: 0.206 AC: 3156 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.270 AC: 937 AN: 3470

East Asian (EAS) AF: 0.151 AC: 781 AN: 5170

South Asian (SAS) AF: 0.237 AC: 1144 AN: 4822

European-Finnish (FIN) AF: 0.218 AC: 2307 AN: 10560

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.261 AC: 17735 AN: 67948

Other (OTH) AF: 0.244 AC: 517 AN: 2116

Alfa AF: 0.240 Hom.: 975

Bravo AF: 0.236

Asia WGS AF: 0.187 AC: 649 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.50
DANN	Benign	0.76
PhyloP100		-1.5
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: rs17264185; hg19: chr15-66997087;