rs12591946

chr15-66781211-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_005585.5(SMAD6):c.1167C>T(p.Phe389=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00611 in 1,608,378 control chromosomes in the GnomAD database, including 625 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (94 hom., cov: 33)
  • Exomes 𝑓: 0.0059 (531 hom.)
• Consequence: SMAD6 NM_005585.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0830

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 15-66781211-C-T is Benign according to our data. Variant chr15-66781211-C-T is described in ClinVar as [Benign]. Clinvar id is 413446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-66781211-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.083 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD6	NM_005585.5	c.1167C>T	p.Phe389=	synonymous_variant	4/4	ENST00000288840.10
SMAD6	XM_011521561.3	c.384C>T	p.Phe128=	synonymous_variant	4/4
SMAD6	NR_027654.2	n.2322C>T		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD6	ENST00000288840.10	c.1167C>T	p.Phe389=	synonymous_variant	4/4	1	NM_005585.5	P1
SMAD6	ENST00000557916.5	c.*282C>T		3_prime_UTR_variant, NMD_transcript_variant	5/5	1
SMAD6	ENST00000559931.5	c.*282C>T		3_prime_UTR_variant, NMD_transcript_variant	4/4	3

Frequencies

GnomAD3 genomes AF: 0.00789 AC: 1201 AN: 152208 Hom.: 94 Cov.: 33

Gnomad AFR AF: 0.00203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.170

Gnomad SAS AF: 0.0244

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.0160 AC: 3837 AN: 240116 Hom.: 279 AF XY: 0.0153 AC XY: 2020 AN XY: 131676

Gnomad AFR exome AF: 0.00247

Gnomad AMR exome AF: 0.000263

Gnomad ASJ exome AF: 0.00272

Gnomad EAS exome AF: 0.176

Gnomad SAS exome AF: 0.0171

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000248

Gnomad OTH exome AF: 0.00927

GnomAD4 exome AF: 0.00592 AC: 8627 AN: 1456052 Hom.: 531 Cov.: 34 AF XY: 0.00615 AC XY: 4456 AN XY: 724716

Gnomad4 AFR exome AF: 0.000897

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00395

Gnomad4 EAS exome AF: 0.146

Gnomad4 SAS exome AF: 0.0176

Gnomad4 FIN exome AF: 0.0000415

Gnomad4 NFE exome AF: 0.000214

Gnomad4 OTH exome AF: 0.0151

GnomAD4 genome AF: 0.00791 AC: 1205 AN: 152326 Hom.: 94 Cov.: 33 AF XY: 0.00866 AC XY: 645 AN XY: 74480

Gnomad4 AFR AF: 0.00202

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00404

Gnomad4 EAS AF: 0.171

Gnomad4 SAS AF: 0.0244

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.00227 Hom.: 6

Bravo AF: 0.00846

Asia WGS AF: 0.103 AC: 356 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jul 21, 2023

- -

Aortic valve disease 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 09, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
Cadd	Benign	10
Dann	Benign	0.80

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

Other links and lift over

dbSNP: rs12591946; hg19: chr15-67073549; COSMIC: COSV56595772;