rs753456441

chr15-66703429-C-Gchr15-66703429-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005585.5(SMAD6):c.171C>G(p.Arg57=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000803 in 1,295,398 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R57R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000092 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000079 (1 hom.)
• Consequence: SMAD6 NM_005585.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.183

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 15-66703429-C-G is Benign according to our data. Variant chr15-66703429-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 471750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.183 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000922 (14/151824) while in subpopulation SAS AF= 0.00269 (13/4828). AF 95% confidence interval is 0.00159. There are 1 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD6	NM_005585.5	c.171C>G	p.Arg57=	synonymous_variant	1/4	ENST00000288840.10
SMAD6	NR_027654.2	n.1194C>G		non_coding_transcript_exon_variant	1/5
SMAD6	XR_931827.3	n.1194C>G		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD6	ENST00000288840.10	c.171C>G	p.Arg57=	synonymous_variant	1/4	1	NM_005585.5	P1
SMAD6	ENST00000557916.5	c.171C>G	p.Arg57=	synonymous_variant, NMD_transcript_variant	1/5	1
SMAD6	ENST00000612349.1	n.353C>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.0000923 AC: 14 AN: 151712 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000787 AC: 90 AN: 1143574 Hom.: 1 Cov.: 32 AF XY: 0.0000966 AC XY: 53 AN XY: 548758

Gnomad4 AFR exome AF: 0.0000432

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00248

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000105

Gnomad4 OTH exome AF: 0.000153

GnomAD4 genome AF: 0.0000922 AC: 14 AN: 151824 Hom.: 1 Cov.: 32 AF XY: 0.000162 AC XY: 12 AN XY: 74230

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

Asia WGS AF: 0.000581 AC: 2 AN: 3458

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 09, 2019

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. -

SMAD6-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 29, 2024

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). -

Aortic valve disease 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jul 03, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
Cadd	Benign	14
Dann	Benign	0.90

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: rs753456441; hg19: chr15-66995767;