15-66762223-C-T

Position:

• chr15-66762223-C-T

Variant summary

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

The NM_005585.5(SMAD6):​c.953-18774C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.487 in 152,072 control chromosomes in the GnomAD database, including 18,574 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 0.49 (18574 hom., cov: 33)
• Consequence: SMAD6 NM_005585.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.74

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]

SMAD6 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.644 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD6	NM_005585.5	c.953-18774C>T		intron_variant		ENST00000288840.10	NP_005576.3
SMAD6	XM_011521561.3	c.170-18774C>T		intron_variant			XP_011519863.1
SMAD6	NR_027654.2	n.2108-18774C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD6	ENST00000288840.10	c.953-18774C>T		intron_variant		1	NM_005585.5	ENSP00000288840.5
SMAD6	ENST00000557916.5	n.*68-18774C>T		intron_variant		1		ENSP00000452955.1
SMAD6	ENST00000559931.5	n.*68-18774C>T		intron_variant		3		ENSP00000453446.1

Frequencies

GnomAD3 genomes AF: 0.487 AC: 74005 AN: 151956 Hom.: 18549 Cov.: 33

Gnomad AFR AF: 0.372

Gnomad AMI AF: 0.511

Gnomad AMR AF: 0.592

Gnomad ASJ AF: 0.507

Gnomad EAS AF: 0.662

Gnomad SAS AF: 0.509

Gnomad FIN AF: 0.544

Gnomad MID AF: 0.439

Gnomad NFE AF: 0.508

Gnomad OTH AF: 0.507

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

GnomAD4 genome AF: 0.487 AC: 74069 AN: 152072 Hom.: 18574 Cov.: 33 AF XY: 0.491 AC XY: 36503 AN XY: 74310

Gnomad4 AFR AF: 0.373

Gnomad4 AMR AF: 0.593

Gnomad4 ASJ AF: 0.507

Gnomad4 EAS AF: 0.662

Gnomad4 SAS AF: 0.508

Gnomad4 FIN AF: 0.544

Gnomad4 NFE AF: 0.508

Gnomad4 OTH AF: 0.507

Alfa AF: 0.511 Hom.: 13527

Bravo AF: 0.489

Asia WGS AF: 0.575 AC: 1996 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.19
DANN	Benign	0.52

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: rs4776831; hg19: chr15-67054561;