NM_005585.5:c.953-17296G>T

Variant names:

• chr15-66763701-G-T
• rs7170982
• NM_005585.5:c.953-17296G>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.953-17296G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.456 in 152,048 control chromosomes in the GnomAD database, including 16,241 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 0.46 (16241 hom., cov: 33)
• Consequence: SMAD6 NM_005585.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.88
• Publications: 3 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=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.625 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD6	NM_005585.5	c.953-17296G>T		intron_variant	Intron 3 of 3	ENST00000288840.10	NP_005576.3
SMAD6	NR_027654.2	n.2108-17296G>T		intron_variant	Intron 4 of 4
SMAD6	XM_011521561.3	c.170-17296G>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.953-17296G>T		intron_variant	Intron 3 of 3	1	NM_005585.5	ENSP00000288840.5
SMAD6	ENST00000557916.5	n.*68-17296G>T		intron_variant	Intron 4 of 4	1		ENSP00000452955.1
SMAD6	ENST00000559931.5	n.*68-17296G>T		intron_variant	Intron 3 of 3	3		ENSP00000453446.1

Frequencies

GnomAD3 genomes AF: 0.456 AC: 69214 AN: 151930 Hom.: 16224 Cov.: 33

Gnomad AFR AF: 0.346

Gnomad AMI AF: 0.509

Gnomad AMR AF: 0.551

Gnomad ASJ AF: 0.451

Gnomad EAS AF: 0.644

Gnomad SAS AF: 0.490

Gnomad FIN AF: 0.539

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.470

Gnomad OTH AF: 0.488

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

GnomAD4 genome AF: 0.456 AC: 69267 AN: 152048 Hom.: 16241 Cov.: 33 AF XY: 0.462 AC XY: 34309 AN XY: 74342

African (AFR) AF: 0.346 AC: 14358 AN: 41466

American (AMR) AF: 0.552 AC: 8440 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.451 AC: 1565 AN: 3472

East Asian (EAS) AF: 0.643 AC: 3317 AN: 5156

South Asian (SAS) AF: 0.488 AC: 2354 AN: 4820

European-Finnish (FIN) AF: 0.539 AC: 5713 AN: 10590

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.470 AC: 31921 AN: 67944

Other (OTH) AF: 0.486 AC: 1025 AN: 2110

Alfa AF: 0.462 Hom.: 2054

Bravo AF: 0.456

Asia WGS AF: 0.513 AC: 1780 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.7
DANN	Benign	0.66
PhyloP100		1.9
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: rs7170982; hg19: chr15-67056039;