rs4776822

Variant names:

• chr15-66702985-G-A
• rs4776822
• NM_005585.5:c.-274G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005585.5(SMAD6):​c.-274G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 313,182 control chromosomes in the GnomAD database, including 8,806 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3849 hom., cov: 32)
  • Exomes 𝑓: 0.24 (4957 hom.)
• Consequence: SMAD6 NM_005585.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.78
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• craniosynostosis 7

  Inheritance: AD, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• radioulnar synostosis, nonsyndromic, susceptibility to

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• aortic valve disease 2

  Inheritance: AD, Unknown Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• familial bicuspid aortic valve

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital radioulnar synostosis

  Inheritance: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet
• congenital heart defects, multiple types

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 15-66702985-G-A is Benign according to our data. Variant chr15-66702985-G-A is described in ClinVar as [Benign]. Clinvar id is 1246802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.256 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD6	NM_005585.5	c.-274G>A		5_prime_UTR_variant	Exon 1 of 4	ENST00000288840.10	NP_005576.3
SMAD6	NR_027654.2	n.750G>A		non_coding_transcript_exon_variant	Exon 1 of 5
SMAD6	XR_931827.3	n.750G>A		non_coding_transcript_exon_variant	Exon 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD6	ENST00000288840.10	c.-274G>A		5_prime_UTR_variant	Exon 1 of 4	1	NM_005585.5	ENSP00000288840.5
SMAD6	ENST00000612349.1	n.-92G>A		upstream_gene_variant		6

Frequencies

GnomAD3 genomes AF: 0.224 AC: 34007 AN: 151834 Hom.: 3852 Cov.: 32

Gnomad AFR AF: 0.184

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.198

Gnomad ASJ AF: 0.256

Gnomad EAS AF: 0.148

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.259

Gnomad OTH AF: 0.233

GnomAD4 exome AF: 0.239 AC: 38600 AN: 161234 Hom.: 4957 Cov.: 0 AF XY: 0.242 AC XY: 19749 AN XY: 81448

African (AFR) AF: 0.178 AC: 876 AN: 4928

American (AMR) AF: 0.158 AC: 692 AN: 4390

Ashkenazi Jewish (ASJ) AF: 0.271 AC: 1705 AN: 6290

East Asian (EAS) AF: 0.222 AC: 3253 AN: 14650

South Asian (SAS) AF: 0.240 AC: 417 AN: 1740

European-Finnish (FIN) AF: 0.216 AC: 3657 AN: 16892

Middle Eastern (MID) AF: 0.303 AC: 260 AN: 858

European-Non Finnish (NFE) AF: 0.250 AC: 25249 AN: 100824

Other (OTH) AF: 0.234 AC: 2491 AN: 10662

GnomAD4 genome AF: 0.224 AC: 34011 AN: 151948 Hom.: 3849 Cov.: 32 AF XY: 0.220 AC XY: 16370 AN XY: 74260

African (AFR) AF: 0.184 AC: 7641 AN: 41504

American (AMR) AF: 0.198 AC: 3029 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 889 AN: 3466

East Asian (EAS) AF: 0.148 AC: 755 AN: 5098

South Asian (SAS) AF: 0.234 AC: 1129 AN: 4822

European-Finnish (FIN) AF: 0.218 AC: 2309 AN: 10580

Middle Eastern (MID) AF: 0.345 AC: 100 AN: 290

European-Non Finnish (NFE) AF: 0.259 AC: 17575 AN: 67874

Other (OTH) AF: 0.233 AC: 492 AN: 2110

Alfa AF: 0.229 Hom.: 521

Bravo AF: 0.218

Asia WGS AF: 0.184 AC: 641 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 04, 2018

GeneDx

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	-0.56
CADD	Benign	18
DANN	Benign	0.96
PhyloP100		1.8
Mutation Taster		=299/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4776822; hg19: chr15-66995323;