rs12906898

Positions:

• chr15-66754458-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.953-26539G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 152,080 control chromosomes in the GnomAD database, including 6,744 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 0.30 (6744 hom., cov: 32)
• Consequence: SMAD6 NM_005585.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.35

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=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.337 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD6	NM_005585.5	c.953-26539G>A		intron_variant		ENST00000288840.10	NP_005576.3
SMAD6	XM_011521561.3	c.170-26539G>A		intron_variant			XP_011519863.1
SMAD6	NR_027654.2	n.2108-26539G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD6	ENST00000288840.10	c.953-26539G>A		intron_variant		1	NM_005585.5	ENSP00000288840	P1
SMAD6	ENST00000557916.5	c.*68-26539G>A		intron_variant, NMD_transcript_variant		1		ENSP00000452955
SMAD6	ENST00000559931.5	c.*68-26539G>A		intron_variant, NMD_transcript_variant		3		ENSP00000453446

Frequencies

GnomAD3 genomes AF: 0.296 AC: 44957 AN: 151962 Hom.: 6736 Cov.: 32

Gnomad AFR AF: 0.341

Gnomad AMI AF: 0.259

Gnomad AMR AF: 0.280

Gnomad ASJ AF: 0.281

Gnomad EAS AF: 0.144

Gnomad SAS AF: 0.223

Gnomad FIN AF: 0.217

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.302

Gnomad OTH AF: 0.290

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

GnomAD4 genome AF: 0.296 AC: 45001 AN: 152080 Hom.: 6744 Cov.: 32 AF XY: 0.290 AC XY: 21584 AN XY: 74384

Gnomad4 AFR AF: 0.341

Gnomad4 AMR AF: 0.280

Gnomad4 ASJ AF: 0.281

Gnomad4 EAS AF: 0.144

Gnomad4 SAS AF: 0.222

Gnomad4 FIN AF: 0.217

Gnomad4 NFE AF: 0.302

Gnomad4 OTH AF: 0.292

Alfa AF: 0.301 Hom.: 6441

Bravo AF: 0.301

Asia WGS AF: 0.254 AC: 885 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.0020
DANN	Benign	0.66

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: rs12906898; hg19: chr15-67046796;