rs755451

Positions:

• chr15-66742613-C-A
• chr15-66742613-C-T

Variant summary

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

The ENST00000288840.10(SMAD6):​c.952+26115C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.532 in 151,854 control chromosomes in the GnomAD database, including 21,778 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 0.53 (21778 hom., cov: 30)
• Consequence: SMAD6 ENST00000288840.10 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.16

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=-1.06).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.707 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD6	NM_005585.5	c.952+26115C>A		intron_variant		ENST00000288840.10	NP_005576.3
SMAD6	XM_011521561.3	c.169+26115C>A		intron_variant			XP_011519863.1
SMAD6	NR_027654.2	n.2107+25473C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD6	ENST00000288840.10	c.952+26115C>A		intron_variant		1	NM_005585.5	ENSP00000288840	P1
SMAD6	ENST00000557916.5	c.*67+25473C>A		intron_variant, NMD_transcript_variant		1		ENSP00000452955
SMAD6	ENST00000559931.5	c.*67+25473C>A		intron_variant, NMD_transcript_variant		3		ENSP00000453446

Frequencies

GnomAD3 genomes AF: 0.532 AC: 80795 AN: 151736 Hom.: 21762 Cov.: 30

Gnomad AFR AF: 0.444

Gnomad AMI AF: 0.611

Gnomad AMR AF: 0.631

Gnomad ASJ AF: 0.562

Gnomad EAS AF: 0.727

Gnomad SAS AF: 0.524

Gnomad FIN AF: 0.558

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.543

Gnomad OTH AF: 0.555

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.532 AC: 80848 AN: 151854 Hom.: 21778 Cov.: 30 AF XY: 0.536 AC XY: 39757 AN XY: 74226

Gnomad4 AFR AF: 0.444

Gnomad4 AMR AF: 0.631

Gnomad4 ASJ AF: 0.562

Gnomad4 EAS AF: 0.727

Gnomad4 SAS AF: 0.524

Gnomad4 FIN AF: 0.558

Gnomad4 NFE AF: 0.543

Gnomad4 OTH AF: 0.557

Alfa AF: 0.542 Hom.: 28459

Bravo AF: 0.539

Asia WGS AF: 0.630 AC: 2188 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.17
DANN	Benign	0.53

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: rs755451; hg19: chr15-67034951;