chr15-66768518-G-A

Position:

• chr15-66768518-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.953-12479G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.294 in 152,082 control chromosomes in the GnomAD database, including 7,588 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 0.29 (7588 hom., cov: 31)
• Consequence: SMAD6 NM_005585.5 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=-0.76).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD6	NM_005585.5	c.953-12479G>A		intron_variant		ENST00000288840.10	NP_005576.3
SMAD6	XM_011521561.3	c.170-12479G>A		intron_variant			XP_011519863.1
SMAD6	NR_027654.2	n.2108-12479G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD6	ENST00000288840.10	c.953-12479G>A		intron_variant		1	NM_005585.5	ENSP00000288840	P1
SMAD6	ENST00000557916.5	c.*68-12479G>A		intron_variant, NMD_transcript_variant		1		ENSP00000452955
SMAD6	ENST00000559931.5	c.*68-12479G>A		intron_variant, NMD_transcript_variant		3		ENSP00000453446

Frequencies

GnomAD3 genomes AF: 0.294 AC: 44650 AN: 151964 Hom.: 7585 Cov.: 31

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.373

Gnomad AMR AF: 0.449

Gnomad ASJ AF: 0.348

Gnomad EAS AF: 0.465

Gnomad SAS AF: 0.409

Gnomad FIN AF: 0.374

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.323

Gnomad OTH AF: 0.347

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

GnomAD4 genome AF: 0.294 AC: 44642 AN: 152082 Hom.: 7588 Cov.: 31 AF XY: 0.302 AC XY: 22444 AN XY: 74340

Gnomad4 AFR AF: 0.124

Gnomad4 AMR AF: 0.450

Gnomad4 ASJ AF: 0.348

Gnomad4 EAS AF: 0.464

Gnomad4 SAS AF: 0.408

Gnomad4 FIN AF: 0.374

Gnomad4 NFE AF: 0.323

Gnomad4 OTH AF: 0.346

Alfa AF: 0.334 Hom.: 12152

Bravo AF: 0.298

Asia WGS AF: 0.367 AC: 1275 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	12
DANN	Benign	0.82

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: rs12906270; hg19: chr15-67060856;