15-66704084-G-C

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.817+9G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000405 in 1,460,496 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 Benign (★★).

Frequency

Genomes: 𝑓 0.0023 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 1 hom. )

Consequence

SMAD6
NM_005585.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.60

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 (BayesDel_noAF=-0.6).

BP6

Variant 15-66704084-G-C is Benign according to our data. Variant chr15-66704084-G-C is described in ClinVar as [Benign]. Clinvar id is 240181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00226 (344/152308) while in subpopulation AFR AF= 0.00786 (327/41582). AF 95% confidence interval is 0.00716. There are 2 homozygotes in gnomad4. There are 152 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 344 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
SMAD6	NM_005585.5 link	c.817+9G>C	intron_variant	Intron 1 of 3	ENST00000288840.10	NP_005576.3	O43541-1
SMAD6	NR_027654.2 link	n.1840+9G>C	intron_variant	Intron 1 of 4
SMAD6	XR_931827.3 link	n.1840+9G>C	intron_variant	Intron 1 of 3
SMAD6	XM_011521561.3 link	c.-4621G>C	upstream_gene_variant			XP_011519863.1	O43541-2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
SMAD6	ENST00000288840.10 link	c.817+9G>C	intron_variant	Intron 1 of 3	1	NM_005585.5	ENSP00000288840.5	O43541-1
SMAD6	ENST00000557916.5 link	n.817+9G>C	intron_variant	Intron 1 of 4	1		ENSP00000452955.1	O43541-4
SMAD6	ENST00000612349.1 link	n.1008G>C	non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

AF:

0.00226

AC:

344

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00789

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000850

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:

0.0000294

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000266

AC:

AN:

71490

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

42552

show subpopulations

Gnomad AFR exome

AF:

0.0120

Gnomad AMR exome

AF:

0.000164

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:

0.0000342

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000189

AC:

247

AN:

1308188

Hom.:

Cov.:

AF XY:

0.000152

AC XY:

AN XY:

646216

show subpopulations

Gnomad4 AFR exome

AF:

0.00775

Gnomad4 AMR exome

AF:

0.000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000141

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000574

Gnomad4 OTH exome

AF:

0.000539

GnomAD4 genome

AF:

0.00226

AC:

344

AN:

152308

Hom.:

Cov.:

AF XY:

0.00204

AC XY:

152

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00786

Gnomad4 AMR

AF:

0.000849

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.00158

Hom.:

Bravo

AF:

0.00244

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Nov 26, 2024

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SMAD6 c.817+9G>C alters a non-conserved nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00027 in 71490 control chromosomes. The observed variant frequency is approximately 8.5 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.817+9G>C 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: 240181). Based on the evidence outlined above, the variant was classified as benign. -

SMAD6-related disorder

Benign:1

Aug 23, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Jan 16, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.73

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