rs12913975

Positions:

• chr15-66764823-G-A

Variant summary

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

The NM_005585.5(SMAD6):​c.953-16174G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 152,186 control chromosomes in the GnomAD database, including 2,822 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 0.18 (2822 hom., cov: 32)
• Consequence: SMAD6 NM_005585.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.43

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=-0.96).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.238 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD6	NM_005585.5	c.953-16174G>A		intron_variant		ENST00000288840.10	NP_005576.3
SMAD6	XM_011521561.3	c.170-16174G>A		intron_variant			XP_011519863.1
SMAD6	NR_027654.2	n.2108-16174G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD6	ENST00000288840.10	c.953-16174G>A		intron_variant		1	NM_005585.5	ENSP00000288840	P1
SMAD6	ENST00000557916.5	c.*68-16174G>A		intron_variant, NMD_transcript_variant		1		ENSP00000452955
SMAD6	ENST00000559931.5	c.*68-16174G>A		intron_variant, NMD_transcript_variant		3		ENSP00000453446

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26786 AN: 152068 Hom.: 2824 Cov.: 32

Gnomad AFR AF: 0.0596

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.127

Gnomad SAS AF: 0.249

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.241

Gnomad OTH AF: 0.198

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

GnomAD4 genome AF: 0.176 AC: 26785 AN: 152186 Hom.: 2822 Cov.: 32 AF XY: 0.174 AC XY: 12962 AN XY: 74408

Gnomad4 AFR AF: 0.0598

Gnomad4 AMR AF: 0.170

Gnomad4 ASJ AF: 0.221

Gnomad4 EAS AF: 0.127

Gnomad4 SAS AF: 0.249

Gnomad4 FIN AF: 0.190

Gnomad4 NFE AF: 0.241

Gnomad4 OTH AF: 0.198

Alfa AF: 0.229 Hom.: 5410

Bravo AF: 0.165

Asia WGS AF: 0.197 AC: 690 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.053
DANN	Benign	0.80

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: rs12913975; hg19: chr15-67057161;