rs138443554

Variant names:

• chr15-66703215-C-T
• rs138443554
• NM_005585.5:c.-44C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_005585.5(SMAD6):​c.-44C>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 0.0196 in 1,318,380 control chromosomes in the GnomAD database, including 333 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (19 hom., cov: 33)
  • Exomes 𝑓: 0.020 (314 hom.)
• Consequence: SMAD6 NM_005585.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.18
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• craniosynostosis 7

  Inheritance: AD, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• radioulnar synostosis, nonsyndromic, susceptibility to

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• aortic valve disease 2

  Inheritance: AD, Unknown Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• familial bicuspid aortic valve

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital radioulnar synostosis

  Inheritance: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet
• congenital heart defects, multiple types

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 15-66703215-C-T is Benign according to our data. Variant chr15-66703215-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1208555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0148 (2255/152178) while in subpopulation NFE AF = 0.0227 (1541/67974). AF 95% confidence interval is 0.0217. There are 19 homozygotes in GnomAd4. There are 1015 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AD,AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD6	NM_005585.5	c.-44C>T		5_prime_UTR_variant	Exon 1 of 4	ENST00000288840.10	NP_005576.3
SMAD6	NR_027654.2	n.980C>T		non_coding_transcript_exon_variant	Exon 1 of 5
SMAD6	XR_931827.3	n.980C>T		non_coding_transcript_exon_variant	Exon 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD6	ENST00000288840.10	c.-44C>T		5_prime_UTR_variant	Exon 1 of 4	1	NM_005585.5	ENSP00000288840.5
SMAD6	ENST00000612349.1	n.139C>T		non_coding_transcript_exon_variant	Exon 1 of 1	6
SMAD6	ENST00000557916.5	n.-44C>T		upstream_gene_variant		1		ENSP00000452955.1

Frequencies

GnomAD3 genomes AF: 0.0148 AC: 2256 AN: 152070 Hom.: 19 Cov.: 33

Gnomad AFR AF: 0.00437

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0178

Gnomad ASJ AF: 0.0438

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00538

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0227

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.0159 AC: 541 AN: 34100 AF XY: 0.0150

Gnomad AFR exome AF: 0.00659

Gnomad AMR exome AF: 0.0119

Gnomad ASJ exome AF: 0.0496

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00731

Gnomad NFE exome AF: 0.0233

Gnomad OTH exome AF: 0.0248

GnomAD4 exome AF: 0.0203 AC: 23628 AN: 1166202 Hom.: 314 Cov.: 21 AF XY: 0.0197 AC XY: 11152 AN XY: 565456

African (AFR) AF: 0.00264 AC: 61 AN: 23110

American (AMR) AF: 0.0146 AC: 157 AN: 10772

Ashkenazi Jewish (ASJ) AF: 0.0437 AC: 741 AN: 16938

East Asian (EAS) AF: 0.0000371 AC: 1 AN: 26960

South Asian (SAS) AF: 0.00169 AC: 77 AN: 45428

European-Finnish (FIN) AF: 0.00839 AC: 344 AN: 40984

Middle Eastern (MID) AF: 0.0102 AC: 32 AN: 3142

European-Non Finnish (NFE) AF: 0.0223 AC: 21267 AN: 952408

Other (OTH) AF: 0.0204 AC: 948 AN: 46460

GnomAD4 genome AF: 0.0148 AC: 2255 AN: 152178 Hom.: 19 Cov.: 33 AF XY: 0.0136 AC XY: 1015 AN XY: 74412

African (AFR) AF: 0.00436 AC: 181 AN: 41530

American (AMR) AF: 0.0177 AC: 271 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0438 AC: 152 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4826

European-Finnish (FIN) AF: 0.00538 AC: 57 AN: 10590

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.0227 AC: 1541 AN: 67974

Other (OTH) AF: 0.0189 AC: 40 AN: 2112

Alfa AF: 0.0162 Hom.: 2

Bravo AF: 0.0153

Asia WGS AF: 0.00145 AC: 5 AN: 3470

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 29, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	19
DANN	Uncertain	0.98
PhyloP100		1.2
Mutation Taster		=286/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs138443554; hg19: chr15-66995553;