rs4776318

Positions:

• chr15-66782319-C-A
• chr15-66782319-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000288840.10(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 ENST00000288840.10 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.422

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 -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/exons	MANE	Protein	UniProt
SMAD6	NM_005585.5	c.*784C>A		3_prime_UTR_variant	4/4	ENST00000288840.10	NP_005576.3
SMAD6	XM_011521561.3	c.*784C>A		3_prime_UTR_variant	4/4		XP_011519863.1
SMAD6	NR_027654.2	n.3430C>A		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD6	ENST00000288840.10	c.*784C>A		3_prime_UTR_variant	4/4	1	NM_005585.5	ENSP00000288840	P1

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

Gnomad4 AFR exome AF: 0.274

Gnomad4 AMR exome AF: 0.353

Gnomad4 ASJ exome AF: 0.458

Gnomad4 EAS exome AF: 0.272

Gnomad4 SAS exome AF: 0.450

Gnomad4 FIN exome AF: 0.374

Gnomad4 NFE exome AF: 0.461

Gnomad4 OTH exome AF: 0.416

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

Gnomad4 AFR AF: 0.276

Gnomad4 AMR AF: 0.379

Gnomad4 ASJ AF: 0.454

Gnomad4 EAS AF: 0.212

Gnomad4 SAS AF: 0.380

Gnomad4 FIN AF: 0.395

Gnomad4 NFE AF: 0.466

Gnomad4 OTH AF: 0.377

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

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: rs4776318; hg19: chr15-67074657;