15-66702492-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_005585.5(SMAD6):c.-767C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 152,224 control chromosomes in the GnomAD database, including 3,625 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.22 (3617 hom., cov: 31)
  • Exomes 𝑓: 0.20 (8 hom.)
• Consequence: SMAD6 NM_005585.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.165

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=-0.34).
• BP6: Variant 15-66702492-C-T is Benign according to our data. Variant chr15-66702492-C-T is described in ClinVar as [Benign]. Clinvar id is 1226059.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-66702492-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.251 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD6	NM_005585.5	c.-767C>T		5_prime_UTR_variant	1/4	ENST00000288840.10
SMAD6	NR_027654.2	n.257C>T		non_coding_transcript_exon_variant	1/5
SMAD6	XR_931827.3	n.257C>T		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD6	ENST00000288840.10	c.-767C>T		5_prime_UTR_variant	1/4	1	NM_005585.5	P1

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32681 AN: 151694 Hom.: 3619 Cov.: 31

Gnomad AFR AF: 0.179

Gnomad AMI AF: 0.100

Gnomad AMR AF: 0.186

Gnomad ASJ AF: 0.255

Gnomad EAS AF: 0.0726

Gnomad SAS AF: 0.205

Gnomad FIN AF: 0.217

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.254

Gnomad OTH AF: 0.224

GnomAD4 exome AF: 0.204 AC: 84 AN: 412 Hom.: 8 Cov.: 0 AF XY: 0.201 AC XY: 49 AN XY: 244

Gnomad4 ASJ exome AF: 0.00

Gnomad4 FIN exome AF: 0.206

Gnomad4 NFE exome AF: 0.222

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.215 AC: 32687 AN: 151812 Hom.: 3617 Cov.: 31 AF XY: 0.211 AC XY: 15679 AN XY: 74188

Gnomad4 AFR AF: 0.179

Gnomad4 AMR AF: 0.186

Gnomad4 ASJ AF: 0.255

Gnomad4 EAS AF: 0.0725

Gnomad4 SAS AF: 0.205

Gnomad4 FIN AF: 0.217

Gnomad4 NFE AF: 0.254

Gnomad4 OTH AF: 0.224

Alfa AF: 0.234 Hom.: 859

Bravo AF: 0.209

Asia WGS AF: 0.139 AC: 485 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 04, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
Cadd	Benign	17
Dann	Uncertain	0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs62005619; hg19: chr15-66994830;