15-66703378-C-A

Position:

chr15-66703378-C-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_005585.5(SMAD6):c.120C>A(p.Gly40Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000246 in 1,455,114 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G40G) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 1 hom. )

Consequence

SMAD6
NM_005585.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.77

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 15-66703378-C-A is Benign according to our data. Variant chr15-66703378-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 240175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.77 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00126 (191/151972) while in subpopulation AFR AF= 0.00448 (186/41476). AF 95% confidence interval is 0.00396. There are 1 homozygotes in gnomad4. There are 81 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 191 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD6	NM_005585.5 linkuse as main transcript	c.120C>A	p.Gly40Gly	synonymous_variant	1/4	ENST00000288840.10	NP_005576.3	O43541-1
SMAD6	NR_027654.2 linkuse as main transcript	n.1143C>A		non_coding_transcript_exon_variant	1/5
SMAD6	XR_931827.3 linkuse as main transcript	n.1143C>A		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.120C>A	p.Gly40Gly	synonymous_variant	1/4	1	NM_005585.5	ENSP00000288840.5	O43541-1
SMAD6	ENST00000557916.5 linkuse as main transcript	n.120C>A		non_coding_transcript_exon_variant	1/5	1		ENSP00000452955.1	O43541-4
SMAD6	ENST00000612349.1 linkuse as main transcript	n.302C>A		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes

AF:

0.00126

AC:

192

AN:

151864

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00452

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000161

AC:

AN:

68238

Hom.:

AF XY:

0.0000795

AC XY:

AN XY:

37758

show subpopulations

Gnomad AFR exome

AF:

0.00717

Gnomad AMR exome

AF:

0.0000857

Gnomad ASJ exome

AF:

0.000214

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000590

GnomAD4 exome

AF:

0.000128

AC:

167

AN:

1303142

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

640812

show subpopulations

Gnomad4 AFR exome

AF:

0.00538

Gnomad4 AMR exome

AF:

0.0000888

Gnomad4 ASJ exome

AF:

0.0000465

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000869

Gnomad4 OTH exome

AF:

0.000301

GnomAD4 genome

AF:

0.00126

AC:

191

AN:

151972

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.00448

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00157

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 21, 2023

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 17, 2022

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. -

SMAD6-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2024

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

Aortic valve disease 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.95

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