15-66703925-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1PP5

The NM_005585.5(SMAD6):c.667C>T(p.Gln223*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000679 in 1,325,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

SMAD6
NM_005585.5 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1O:1

Conservation

PhyloP100: 3.74

Publications

1 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):

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

SMAD6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 15-66703925-C-T is Pathogenic according to our data. Variant chr15-66703925-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 417818.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SMAD6	NM_005585.5 link	c.667C>T	p.Gln223*	stop_gained	Exon 1 of 4	ENST00000288840.10	NP_005576.3
SMAD6	NR_027654.2 link	n.1690C>T		non_coding_transcript_exon_variant	Exon 1 of 5
SMAD6	XR_931827.3 link	n.1690C>T		non_coding_transcript_exon_variant	Exon 1 of 4
SMAD6	XM_011521561.3 link	c.-4780C>T		upstream_gene_variant			XP_011519863.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SMAD6	ENST00000288840.10 link	c.667C>T	p.Gln223*	stop_gained	Exon 1 of 4	1	NM_005585.5	ENSP00000288840.5
SMAD6	ENST00000557916.5 link	n.667C>T		non_coding_transcript_exon_variant	Exon 1 of 5	1		ENSP00000452955.1
SMAD6	ENST00000612349.1 link	n.849C>T		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151708

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

30436

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000682

AC:

AN:

1173880

Hom.:

Cov.:

AF XY:

0.00000525

AC XY:

AN XY:

571728

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23978

American (AMR)

AF:

0.00

AC:

AN:

12392

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17384

East Asian (EAS)

AF:

0.00

AC:

AN:

26672

South Asian (SAS)

AF:

0.00

AC:

AN:

42804

European-Finnish (FIN)

AF:

0.0000373

AC:

AN:

26840

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3434

European-Non Finnish (NFE)

AF:

0.00000617

AC:

AN:

973040

Other (OTH)

AF:

0.0000211

AC:

AN:

47336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.00000659

AC:

AN:

151708

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74090

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41398

American (AMR)

AF:

0.00

AC:

AN:

15230

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67894

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Oct 01, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in an individual with metopic craniosynostosis; the variant was inherited from the unaffected father and also present in an unaffected sibling (PMID: 27606499); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27606499) -

Aortic valve disease 2

Uncertain:1

Nov 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Gln223*) in the SMAD6 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in SMAD6 cause disease. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with non-syndromic midline craniosynostosis (PMID: 27606499). ClinVar contains an entry for this variant (Variation ID: 417818). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

CRANIOSYNOSTOSIS 7, SUSCEPTIBILITY TO

Other:1

Apr 19, 2017

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.80

PhyloP100

3.7

Vest4

0.83

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Mutation Taster

=1/199

disease causing (fs/PTC)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over