chr15-66703333-C-T

Position:

chr15-66703333-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The NM_005585.5(SMAD6):c.75C>T(p.Gly25=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 1,482,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

SMAD6
NM_005585.5 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.361

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.37).

BP6

Variant 15-66703333-C-T is Benign according to our data. Variant chr15-66703333-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 405512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-66703333-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.361 with no splicing effect.

BS2

High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SMAD6	NM_005585.5 linkuse as main transcript	c.75C>T	p.Gly25=	synonymous_variant	1/4	ENST00000288840.10	NP_005576.3
SMAD6	NR_027654.2 linkuse as main transcript	n.1098C>T		non_coding_transcript_exon_variant	1/5
SMAD6	XR_931827.3 linkuse as main transcript	n.1098C>T		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD6	ENST00000288840.10 linkuse as main transcript	c.75C>T	p.Gly25=	synonymous_variant	1/4	1	NM_005585.5	ENSP00000288840	P1	O43541-1
SMAD6	ENST00000557916.5 linkuse as main transcript	c.75C>T	p.Gly25=	synonymous_variant, NMD_transcript_variant	1/5	1		ENSP00000452955		O43541-4
SMAD6	ENST00000612349.1 linkuse as main transcript	n.257C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

AF:

0.0000922

AC:

AN:

151802

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

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:

0.000192

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000972

AC:

AN:

92562

Hom.:

AF XY:

0.000116

AC XY:

AN XY:

51660

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000132

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000209

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000144

AC:

191

AN:

1330934

Hom.:

Cov.:

AF XY:

0.000154

AC XY:

101

AN XY:

656634

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000755

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000178

Gnomad4 OTH exome

AF:

0.0000367

GnomAD4 genome

AF:

0.0000922

AC:

AN:

151802

Hom.:

Cov.:

AF XY:

0.0000809

AC XY:

AN XY:

74138

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000192

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000855

Hom.:

Bravo

AF:

0.000113

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

SMAD6-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 17, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 30, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Aortic valve disease 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 20, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

0.98

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over