rs188799901

Positions:

chr15-66703319-G-A

Variant summary

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

The NM_005585.5(SMAD6):c.61G>A(p.Asp21Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00617 in 1,487,510 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0050 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0063 ( 46 hom. )

Consequence

SMAD6
NM_005585.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 4.16

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=0.0061695874).

BP6

Variant 15-66703319-G-A is Benign according to our data. Variant chr15-66703319-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 413448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-66703319-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00495 (753/152112) while in subpopulation AMR AF= 0.00713 (109/15294). AF 95% confidence interval is 0.00604. There are 3 homozygotes in gnomad4. There are 414 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 753 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD6	NM_005585.5 linkuse as main transcript	c.61G>A	p.Asp21Asn	missense_variant	1/4	ENST00000288840.10	NP_005576.3	O43541-1
SMAD6	NR_027654.2 linkuse as main transcript	n.1084G>A		non_coding_transcript_exon_variant	1/5
SMAD6	XR_931827.3 linkuse as main transcript	n.1084G>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.61G>A	p.Asp21Asn	missense_variant	1/4	1	NM_005585.5	ENSP00000288840.5	O43541-1
SMAD6	ENST00000557916.5 linkuse as main transcript	n.61G>A		non_coding_transcript_exon_variant	1/5	1		ENSP00000452955.1	O43541-4
SMAD6	ENST00000612349.1 linkuse as main transcript	n.243G>A		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes

AF:

0.00496

AC:

754

AN:

152004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000893

Gnomad AMI

AF:

0.00659

Gnomad AMR

AF:

0.00714

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00435

Gnomad FIN

AF:

0.0149

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00611

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00506

AC:

497

AN:

98162

Hom.:

AF XY:

0.00510

AC XY:

278

AN XY:

54538

show subpopulations

Gnomad AFR exome

AF:

0.000496

Gnomad AMR exome

AF:

0.00235

Gnomad ASJ exome

AF:

0.00132

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00340

Gnomad FIN exome

AF:

0.0127

Gnomad NFE exome

AF:

0.00555

Gnomad OTH exome

AF:

0.00198

GnomAD4 exome

AF:

0.00631

AC:

8420

AN:

1335398

Hom.:

Cov.:

AF XY:

0.00626

AC XY:

4124

AN XY:

658916

show subpopulations

Gnomad4 AFR exome

AF:

0.000927

Gnomad4 AMR exome

AF:

0.00296

Gnomad4 ASJ exome

AF:

0.000599

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00336

Gnomad4 FIN exome

AF:

0.0133

Gnomad4 NFE exome

AF:

0.00677

Gnomad4 OTH exome

AF:

0.00570

GnomAD4 genome

AF:

0.00495

AC:

753

AN:

152112

Hom.:

Cov.:

AF XY:

0.00557

AC XY:

414

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.000891

Gnomad4 AMR

AF:

0.00713

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00414

Gnomad4 FIN

AF:

0.0149

Gnomad4 NFE

AF:

0.00611

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00559

Hom.:

Bravo

AF:

0.00386

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.00116

AC:

ESP6500EA

AF:

0.00310

AC:

ExAC

AF:

0.00223

AC:

226

Asia WGS

AF:

0.000867

AC:

AN:

3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 2020	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	SMAD6: PP2, BS1, BS2 -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Apr 04, 2023

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 30, 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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.48

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.84

MetaRNN

Benign

0.0062

MetaSVM

Benign

-0.67

MutationAssessor

Benign

1.7

PrimateAI

Pathogenic

0.95

PROVEAN

Benign

-0.73

REVEL

Benign

0.27

Sift

Uncertain

0.0040

Sift4G

Benign

0.095

Polyphen

0.84

Vest4

0.21

MVP

0.75

MPC

1.8

ClinPred

0.024

GERP RS

3.8

Varity_R

0.19

gMVP

0.36

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