chr15-66703969-C-T

Position:

chr15-66703969-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_005585.5(SMAD6):c.711C>T(p.His237His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00826 in 1,448,960 control chromosomes in the GnomAD database, including 228 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0073 ( 25 hom., cov: 33)

Exomes 𝑓: 0.0084 ( 203 hom. )

Consequence

SMAD6
NM_005585.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.97

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:

SMAD6 (HGNC:):

SMAD6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant 15-66703969-C-T is Benign according to our data. Variant chr15-66703969-C-T is described in ClinVar as [Benign]. Clinvar id is 413445.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-66703969-C-T is described in Lovd as [Benign]. Variant chr15-66703969-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=1.97 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0703 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD6	NM_005585.5 linkuse as main transcript	c.711C>T	p.His237His	synonymous_variant	1/4	ENST00000288840.10	NP_005576.3	O43541-1
SMAD6	NR_027654.2 linkuse as main transcript	n.1734C>T		non_coding_transcript_exon_variant	1/5
SMAD6	XR_931827.3 linkuse as main transcript	n.1734C>T		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SMAD6	ENST00000288840.10 linkuse as main transcript	c.711C>T	p.His237His	synonymous_variant	1/4	1	NM_005585.5	ENSP00000288840.5	O43541-1
SMAD6	ENST00000557916.5 linkuse as main transcript	n.711C>T		non_coding_transcript_exon_variant	1/5	1		ENSP00000452955.1	O43541-4
SMAD6	ENST00000612349.1 linkuse as main transcript	n.893C>T		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes

AF:

0.00733

AC:

1115

AN:

152020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0115

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.0767

Gnomad SAS

AF:

0.0294

Gnomad FIN

AF:

0.000757

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00478

Gnomad OTH

AF:

0.00959

GnomAD3 exomes

AF:

0.0120

AC:

904

AN:

75040

Hom.:

AF XY:

0.0119

AC XY:

518

AN XY:

43524

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0157

Gnomad ASJ exome

AF:

0.000461

Gnomad EAS exome

AF:

0.0758

Gnomad SAS exome

AF:

0.0208

Gnomad FIN exome

AF:

0.000850

Gnomad NFE exome

AF:

0.00505

Gnomad OTH exome

AF:

0.00473

GnomAD4 exome

AF:

0.00838

AC:

10862

AN:

1296830

Hom.:

203

Cov.:

AF XY:

0.00863

AC XY:

5518

AN XY:

639630

show subpopulations

Gnomad4 AFR exome

AF:

0.00124

Gnomad4 AMR exome

AF:

0.0131

Gnomad4 ASJ exome

AF:

0.000569

Gnomad4 EAS exome

AF:

0.102

Gnomad4 SAS exome

AF:

0.0220

Gnomad4 FIN exome

AF:

0.00106

Gnomad4 NFE exome

AF:

0.00539

Gnomad4 OTH exome

AF:

0.00870

GnomAD4 genome

AF:

0.00731

AC:

1112

AN:

152130

Hom.:

Cov.:

AF XY:

0.00811

AC XY:

603

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00108

Gnomad4 AMR

AF:

0.0114

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.0765

Gnomad4 SAS

AF:

0.0292

Gnomad4 FIN

AF:

0.000757

Gnomad4 NFE

AF:

0.00478

Gnomad4 OTH

AF:

0.00949

Alfa

AF:

0.00492

Hom.:

Bravo

AF:

0.00760

Asia WGS

AF:

0.0450

AC:

156

AN:

3466

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 21, 2023	- -

Aortic valve disease 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

0.98

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

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