rs374058045

Positions:

chr15-66703337-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005585.5(SMAD6):c.79A>G(p.Ser27Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000247 in 1,484,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

SMAD6
NM_005585.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.162

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005714625).

BP6

Variant 15-66703337-A-G is Benign according to our data. Variant chr15-66703337-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 539113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-66703337-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00129 (196/151824) while in subpopulation AFR AF= 0.00456 (189/41484). AF 95% confidence interval is 0.00402. There are 0 homozygotes in gnomad4. There are 98 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 196 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD6	NM_005585.5 linkuse as main transcript	c.79A>G	p.Ser27Gly	missense_variant	1/4	ENST00000288840.10	NP_005576.3	O43541-1
SMAD6	NR_027654.2 linkuse as main transcript	n.1102A>G		non_coding_transcript_exon_variant	1/5
SMAD6	XR_931827.3 linkuse as main transcript	n.1102A>G		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.79A>G	p.Ser27Gly	missense_variant	1/4	1	NM_005585.5	ENSP00000288840.5	O43541-1
SMAD6	ENST00000557916.5 linkuse as main transcript	n.79A>G		non_coding_transcript_exon_variant	1/5	1		ENSP00000452955.1	O43541-4
SMAD6	ENST00000612349.1 linkuse as main transcript	n.261A>G		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes

AF:

0.00129

AC:

196

AN:

151716

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00457

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000442

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.0000653

AC:

AN:

91820

Hom.:

AF XY:

0.0000391

AC XY:

AN XY:

51196

show subpopulations

Gnomad AFR exome

AF:

0.00254

Gnomad AMR exome

AF:

0.0000669

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000449

Gnomad SAS 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:

0.000128

AC:

170

AN:

1332902

Hom.:

Cov.:

AF XY:

0.000117

AC XY:

AN XY:

657458

show subpopulations

Gnomad4 AFR exome

AF:

0.00468

Gnomad4 AMR exome

AF:

0.000149

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000105

Gnomad4 SAS exome

AF:

0.0000137

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000257

Gnomad4 OTH exome

AF:

0.000183

GnomAD4 genome

AF:

0.00129

AC:

196

AN:

151824

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

AN XY:

74218

show subpopulations

Gnomad4 AFR

AF:

0.00456

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000442

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.000578

Hom.:

Bravo

AF:

0.00162

ESP6500AA

AF:

0.000629

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000214

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

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

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 28, 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. -

Aortic valve disease 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.046

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.48

CADD

Benign

6.4

DANN

Benign

0.78

DEOGEN2

Benign

0.26

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.062

LIST_S2

Benign

0.28

M_CAP

Pathogenic

0.32

MetaRNN

Benign

0.0057

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.0

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.080

REVEL

Benign

0.059

Sift

Benign

0.97

Sift4G

Benign

0.55

Polyphen

0.0

Vest4

0.11

MVP

0.43

MPC

1.0

ClinPred

0.0090

GERP RS

2.6

Varity_R

0.043

gMVP

0.17

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