rs17264185

chr15-66704749-A-G

Variant summary

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

The NM_005585.5(SMAD6):c.817+674A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 152,122 control chromosomes in the GnomAD database, including 4,399 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 0.24 (4397 hom., cov: 32)
  • Exomes 𝑓: 0.22 (2 hom.)
• Consequence: SMAD6 NM_005585.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.54

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=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.258 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD6	NM_005585.5	c.817+674A>G		intron_variant		ENST00000288840.10
SMAD6	XM_011521561.3	c.-3956A>G		5_prime_UTR_variant	1/4
SMAD6	NR_027654.2	n.1840+674A>G		intron_variant, non_coding_transcript_variant
SMAD6	XR_931827.3	n.1840+674A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD6	ENST00000288840.10	c.817+674A>G		intron_variant		1	NM_005585.5	P1
SMAD6	ENST00000557916.5	c.817+674A>G		intron_variant, NMD_transcript_variant		1
SMAD6	ENST00000612349.1	n.1673A>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.239 AC: 36356 AN: 151932 Hom.: 4399 Cov.: 32

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.270

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.237

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.261

Gnomad OTH AF: 0.245

GnomAD4 exome AF: 0.222 AC: 16 AN: 72 Hom.: 2 Cov.: 0 AF XY: 0.241 AC XY: 13 AN XY: 54

Gnomad4 AFR exome AF: 0.500

Gnomad4 AMR exome AF: 0.00

Gnomad4 FIN exome AF: 0.0714

Gnomad4 NFE exome AF: 0.304

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.239 AC: 36360 AN: 152050 Hom.: 4397 Cov.: 32 AF XY: 0.236 AC XY: 17549 AN XY: 74320

Gnomad4 AFR AF: 0.231

Gnomad4 AMR AF: 0.206

Gnomad4 ASJ AF: 0.270

Gnomad4 EAS AF: 0.151

Gnomad4 SAS AF: 0.237

Gnomad4 FIN AF: 0.218

Gnomad4 NFE AF: 0.261

Gnomad4 OTH AF: 0.244

Alfa AF: 0.239 Hom.: 950

Bravo AF: 0.236

Asia WGS AF: 0.187 AC: 649 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.50
Dann	Benign	0.76

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: rs17264185; hg19: chr15-66997087;