chr15-66781000-C-T

Variant names:

Variant summary

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

The NM_005585.5(SMAD6):c.956C>T(p.Ala319Val) variant causes a missense change. The variant allele was found at a frequency of 0.000297 in 1,569,058 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00030 ( 3 hom. )

Consequence

SMAD6
NM_005585.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.06

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014975667).

BP6

Variant 15-66781000-C-T is Benign according to our data. Variant chr15-66781000-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 413451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000249 (38/152330) while in subpopulation SAS AF= 0.00228 (11/4830). AF 95% confidence interval is 0.00128. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 38 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD6	NM_005585.5 link	c.956C>T	p.Ala319Val	missense_variant	Exon 4 of 4	ENST00000288840.10	NP_005576.3	O43541-1
SMAD6	XM_011521561.3 link	c.173C>T	p.Ala58Val	missense_variant	Exon 4 of 4		XP_011519863.1	O43541-2
SMAD6	NR_027654.2 link	n.2111C>T		non_coding_transcript_exon_variant	Exon 5 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD6	ENST00000288840.10 link	c.956C>T	p.Ala319Val	missense_variant	Exon 4 of 4	1	NM_005585.5	ENSP00000288840.5		O43541-1

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000461

AC:

AN:

195368

Hom.:

AF XY:

0.000502

AC XY:

AN XY:

107502

show subpopulations

Gnomad AFR exome

AF:

0.000172

Gnomad AMR exome

AF:

0.000129

Gnomad ASJ exome

AF:

0.000109

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00166

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000375

Gnomad OTH exome

AF:

0.00116

GnomAD4 exome

AF:

0.000302

AC:

428

AN:

1416728

Hom.:

Cov.:

AF XY:

0.000344

AC XY:

241

AN XY:

701536

show subpopulations

Gnomad4 AFR exome

AF:

0.0000308

Gnomad4 AMR exome

AF:

0.000216

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000266

Gnomad4 SAS exome

AF:

0.00160

Gnomad4 FIN exome

AF:

0.000107

Gnomad4 NFE exome

AF:

0.000208

Gnomad4 OTH exome

AF:

0.000509

GnomAD4 genome

AF:

0.000249

AC:

AN:

152330

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000338

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000398

Hom.:

Bravo

AF:

0.000332

ESP6500AA

AF:

0.000456

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000449

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

SMAD6-related disorder

Benign:1

Aug 29, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Feb 17, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SMAD6: BS1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

0.060

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.077

MetaRNN

Benign

0.015

MetaSVM

Uncertain

0.70

MutationAssessor

Benign

1.3

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.2

REVEL

Uncertain

0.53

Sift

Benign

0.035

Sift4G

Benign

0.075

Polyphen

0.85

Vest4

0.080

MVP

0.90

MPC

0.29

ClinPred

0.024

GERP RS

5.6

Varity_R

0.14

gMVP

0.37

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