rs769605183

chr15-66703331-GGCGGCA-Gchr15-66703331-GGCGGCA-GGCGGCAGCGGCA

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_005585.5(SMAD6):c.79_84del(p.Ser27_Gly28del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000553 in 1,485,660 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G25G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00055 (0 hom.)
• Consequence: SMAD6 NM_005585.5 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 3.63

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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000559 (85/152132) while in subpopulation AMR AF= 0.00131 (20/15300). AF 95% confidence interval is 0.000866. There are 0 homozygotes in gnomad4. There are 46 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 85 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD6	NM_005585.5	c.79_84del	p.Ser27_Gly28del	inframe_deletion	1/4	ENST00000288840.10
SMAD6	NR_027654.2	n.1102_1107del		non_coding_transcript_exon_variant	1/5
SMAD6	XR_931827.3	n.1102_1107del		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD6	ENST00000288840.10	c.79_84del	p.Ser27_Gly28del	inframe_deletion	1/4	1	NM_005585.5	P1
SMAD6	ENST00000557916.5	c.79_84del	p.Ser27_Gly28del	inframe_deletion, NMD_transcript_variant	1/5	1
SMAD6	ENST00000612349.1	n.261_266del		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.000559 AC: 85 AN: 152024 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000946

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000853

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000247 AC: 23 AN: 92970 Hom.: 0 AF XY: 0.000173 AC XY: 9 AN XY: 51878

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000327

Gnomad ASJ exome AF: 0.000300

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000592

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000388

Gnomad OTH exome AF: 0.000838

GnomAD4 exome AF: 0.000553 AC: 737 AN: 1333528 Hom.: 0 AF XY: 0.000564 AC XY: 371 AN XY: 657798

Gnomad4 AFR exome AF: 0.000112

Gnomad4 AMR exome AF: 0.000675

Gnomad4 ASJ exome AF: 0.000258

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000275

Gnomad4 FIN exome AF: 0.0000850

Gnomad4 NFE exome AF: 0.000644

Gnomad4 OTH exome AF: 0.000494

GnomAD4 genome AF: 0.000559 AC: 85 AN: 152132 Hom.: 0 Cov.: 32 AF XY: 0.000618 AC XY: 46 AN XY: 74382

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000946

Gnomad4 NFE AF: 0.000854

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000978 Hom.: 0

Bravo AF: 0.000518

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 27, 2023

Variant summary: SMAD6 c.79_84delAGCGGC (p.Ser27_Gly28del) results in an in-frame deletion that is predicted to remove two amino acids from the encoded protein. The variant allele was found at a frequency of 0.00025 in 92970 control chromosomes. The observed variant frequency is approximately 8 fold of the estimated maximal expected allele frequency for a pathogenic variant in SMAD6 causing Aortic Valve Disease phenotype (3.1e-05), strongly suggesting that the variant is benign. c.79_84delAGCGGC has been reported in the literature in individuals affected with Aortic Valve Disease (Gillis_2017). This report does not provide unequivocal conclusions about association of the variant with Aortic Valve Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 28659821). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Aortic valve disease 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 16, 2024

This variant, c.79_84del, results in the deletion of 2 amino acid(s) of the SMAD6 protein (p.Ser27_Gly28del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs769605183, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with SMAD6-related conditions (PMID: 28659821, 32499606). ClinVar contains an entry for this variant (Variation ID: 471762). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 25, 2021

Reported in a patient with bicuspid aortic valve who also harbors a variant in the NOTCH1 gene (Gillis et al., 2017); In-frame deletion of two amino acids in a non-repeat region; In silico analysis supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32499606, 30848080, 28659821) -

Aortic valve disease 2;C4479496:Craniosynostosis 7 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 06, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs769605183; hg19: chr15-66995669;