15-66782319-C-A

Variant names:

• chr15-66782319-C-A
• rs4776318
• NM_005585.5:c.*784C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005585.5(SMAD6):​c.*784C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.393 in 170,680 control chromosomes in the GnomAD database, including 13,745 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.39 (11912 hom., cov: 32)
  • Exomes 𝑓: 0.43 (1833 hom.)
• Consequence: SMAD6 NM_005585.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.422
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.462 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD6	NM_005585.5	c.*784C>A		3_prime_UTR_variant	Exon 4 of 4	ENST00000288840.10	NP_005576.3
SMAD6	NR_027654.2	n.3430C>A		non_coding_transcript_exon_variant	Exon 5 of 5
SMAD6	XM_011521561.3	c.*784C>A		3_prime_UTR_variant	Exon 4 of 4		XP_011519863.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD6	ENST00000288840.10	c.*784C>A		3_prime_UTR_variant	Exon 4 of 4	1	NM_005585.5	ENSP00000288840.5

Frequencies

GnomAD3 genomes AF: 0.388 AC: 58836 AN: 151776 Hom.: 11902 Cov.: 32

Gnomad AFR AF: 0.276

Gnomad AMI AF: 0.423

Gnomad AMR AF: 0.380

Gnomad ASJ AF: 0.454

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.379

Gnomad FIN AF: 0.395

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.466

Gnomad OTH AF: 0.376

GnomAD4 exome AF: 0.433 AC: 8130 AN: 18786 Hom.: 1833 Cov.: 0 AF XY: 0.434 AC XY: 4136 AN XY: 9532

African (AFR) AF: 0.274 AC: 232 AN: 848

American (AMR) AF: 0.353 AC: 214 AN: 606

Ashkenazi Jewish (ASJ) AF: 0.458 AC: 385 AN: 840

East Asian (EAS) AF: 0.272 AC: 274 AN: 1006

South Asian (SAS) AF: 0.450 AC: 72 AN: 160

European-Finnish (FIN) AF: 0.374 AC: 226 AN: 604

Middle Eastern (MID) AF: 0.420 AC: 47 AN: 112

European-Non Finnish (NFE) AF: 0.461 AC: 6122 AN: 13268

Other (OTH) AF: 0.416 AC: 558 AN: 1342

GnomAD4 genome AF: 0.388 AC: 58868 AN: 151894 Hom.: 11912 Cov.: 32 AF XY: 0.381 AC XY: 28297 AN XY: 74188

African (AFR) AF: 0.276 AC: 11447 AN: 41438

American (AMR) AF: 0.379 AC: 5784 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.454 AC: 1574 AN: 3470

East Asian (EAS) AF: 0.212 AC: 1095 AN: 5168

South Asian (SAS) AF: 0.380 AC: 1830 AN: 4816

European-Finnish (FIN) AF: 0.395 AC: 4155 AN: 10510

Middle Eastern (MID) AF: 0.439 AC: 129 AN: 294

European-Non Finnish (NFE) AF: 0.466 AC: 31676 AN: 67918

Other (OTH) AF: 0.377 AC: 794 AN: 2104

Alfa AF: 0.418 Hom.: 2414

Bravo AF: 0.375

Asia WGS AF: 0.344 AC: 1203 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.7
DANN	Benign	0.34
PhyloP100		0.42

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: rs4776318; hg19: chr15-67074657;