Genetic Variant SMAD6:c.952+24315T>C (chr15-66740813-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005585.5(SMAD6):c.952+24315T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.782 in 152,172 control chromosomes in the GnomAD database, including 46,871 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 0.78 ( 46869 hom., cov: 32)

Exomes 𝑓: 0.57 ( 2 hom. )

Consequence

SMAD6
NM_005585.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.323

Publications

33 publications found

Variant links:

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):

syndromic craniosynostosis
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
craniosynostosis 7
Inheritance: AD, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
radioulnar synostosis, nonsyndromic, susceptibility to
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, Ambry Genetics
aortic valve disease 2
Inheritance: Unknown, AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
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

SMAD6 links:

ENSG00000274995 (HGNC:):

ENSG00000274995 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.931 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD6	NM_005585.5	MANE Select	c.952+24315T>C		intron	N/A	NP_005576.3
	SMAD6	NR_027654.2		n.2107+23673T>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SMAD6	ENST00000288840.10	TSL:1 MANE Select	c.952+24315T>C	intron	N/A	ENSP00000288840.5	O43541-1
SMAD6	ENST00000557916.5	TSL:1	n.*67+23673T>C	intron	N/A	ENSP00000452955.1	O43541-4
SMAD6	ENST00000966143.1		c.874+29089T>C	intron	N/A	ENSP00000636202.1

Frequencies

GnomAD3 genomes

AF:

0.782

AC:

118829

AN:

152040

Hom.:

46817

Cov.:

show subpopulations

Gnomad AFR

AF:

0.870

Gnomad AMI

AF:

0.835

Gnomad AMR

AF:

0.807

Gnomad ASJ

AF:

0.702

Gnomad EAS

AF:

0.953

Gnomad SAS

AF:

0.762

Gnomad FIN

AF:

0.759

Gnomad MID

AF:

0.642

Gnomad NFE

AF:

0.718

Gnomad OTH

AF:

0.782

GnomAD4 exome

AF:

0.571

AC:

AN:

Hom.:

Cov.:

AF XY:

0.500

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.500

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.500

AC:

AN:

Other (OTH)

AF:

1.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.782

AC:

118942

AN:

152158

Hom.:

46869

Cov.:

AF XY:

0.785

AC XY:

58404

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.870

AC:

36132

AN:

41534

American (AMR)

AF:

0.808

AC:

12348

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.702

AC:

2430

AN:

3464

East Asian (EAS)

AF:

0.953

AC:

4939

AN:

5182

South Asian (SAS)

AF:

0.762

AC:

3665

AN:

4812

European-Finnish (FIN)

AF:

0.759

AC:

8030

AN:

10584

Middle Eastern (MID)

AF:

0.643

AC:

189

AN:

294

European-Non Finnish (NFE)

AF:

0.718

AC:

48798

AN:

67978

Other (OTH)

AF:

0.782

AC:

1651

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1330

2660

3990

5320

6650

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

862

1724

2586

3448

4310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.737

Hom.:

76627

Bravo

AF:

0.791

Asia WGS

AF:

0.851

AC:

2960

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

5.0

(source)

DANN

Benign

0.53

PhyloP100

-0.32

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over