rs368960350

Positions:

chr15-66703397-C-T

Variant summary

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

The NM_005585.5(SMAD6):c.139C>T(p.Pro47Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000913 in 1,404,954 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0050 ( 6 hom., cov: 32)

Exomes 𝑓: 0.00042 ( 3 hom. )

Consequence

SMAD6
NM_005585.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.55

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005159676).

BP6

Variant 15-66703397-C-T is Benign according to our data. Variant chr15-66703397-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 471749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-66703397-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00501 (762/151958) while in subpopulation AFR AF= 0.0176 (729/41478). AF 95% confidence interval is 0.0165. There are 6 homozygotes in gnomad4. There are 342 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 762 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD6	NM_005585.5 linkuse as main transcript	c.139C>T	p.Pro47Ser	missense_variant	1/4	ENST00000288840.10	NP_005576.3	O43541-1
SMAD6	NR_027654.2 linkuse as main transcript	n.1162C>T		non_coding_transcript_exon_variant	1/5
SMAD6	XR_931827.3 linkuse as main transcript	n.1162C>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.139C>T	p.Pro47Ser	missense_variant	1/4	1	NM_005585.5	ENSP00000288840.5	O43541-1
SMAD6	ENST00000557916.5 linkuse as main transcript	n.139C>T		non_coding_transcript_exon_variant	1/5	1		ENSP00000452955.1	O43541-4
SMAD6	ENST00000612349.1 linkuse as main transcript	n.321C>T		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes

AF:

0.00500

AC:

759

AN:

151850

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0176

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000736

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.000812

AC:

AN:

33256

Hom.:

AF XY:

0.000441

AC XY:

AN XY:

18142

show subpopulations

Gnomad AFR exome

AF:

0.0361

Gnomad AMR exome

AF:

0.00178

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000416

AC:

521

AN:

1252996

Hom.:

Cov.:

AF XY:

0.000375

AC XY:

230

AN XY:

613124

show subpopulations

Gnomad4 AFR exome

AF:

0.0176

Gnomad4 AMR exome

AF:

0.00110

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000692

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000693

Gnomad4 OTH exome

AF:

0.00108

GnomAD4 genome

AF:

0.00501

AC:

762

AN:

151958

Hom.:

Cov.:

AF XY:

0.00460

AC XY:

342

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.0176

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000736

Gnomad4 OTH

AF:

0.00332

Alfa

AF:

0.00354

Hom.:

Bravo

AF:

0.00581

ESP6500AA

AF:

0.00823

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000559

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3470

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jun 04, 2024

Variant summary: SMAD6 c.139C>T (p.Pro47Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00081 in 33256 control chromosomes. The observed variant frequency is approximately 26-fold of the estimated maximal expected allele frequency for a pathogenic variant in SMAD6 causing Aortic Valve Disease phenotype (3.1e-05). To our knowledge, no occurrence of c.139C>T in individuals affected with Aortic Valve Disease and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 471749). Based on the evidence outlined above, the variant was classified as likely benign. -

Aortic valve disease 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.54

MetaRNN

Benign

0.0052

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.7

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.88

REVEL

Benign

0.12

Sift

Uncertain

0.012

Sift4G

Benign

0.39

Polyphen

0.0030

Vest4

0.17

MVP

0.59

MPC

1.1

ClinPred

0.021

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.077

gMVP

0.42

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