15-66703378-C-T

Variant names:

• chr15-66703378-C-T
• rs149612008
• NM_005585.5:c.120C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005585.5(SMAD6):​c.120C>T​(p.Gly40Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0363 in 1,454,994 control chromosomes in the GnomAD database, including 1,154 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G40G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.029 (91 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1063 hom.)
• Consequence: SMAD6 NM_005585.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.77
• Publications: 3 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):

• syndromic craniosynostosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• craniosynostosis 7

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

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

  Inheritance: Unknown, AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 15-66703378-C-T is Benign according to our data. Variant chr15-66703378-C-T is described in ClinVar as Benign. ClinVar VariationId is 240176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.77 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0295 (4479/151964) while in subpopulation NFE AF = 0.0436 (2961/67898). AF 95% confidence interval is 0.0423. There are 91 homozygotes in GnomAd4. There are 2189 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 91 AD,Unknown,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005585.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD6	NM_005585.5	MANE Select	c.120C>T	p.Gly40Gly	synonymous	Exon 1 of 4	NP_005576.3
	SMAD6	NR_027654.2		n.1143C>T		non_coding_transcript_exon	Exon 1 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD6	ENST00000288840.10	TSL:1 MANE Select	c.120C>T	p.Gly40Gly	synonymous	Exon 1 of 4	ENSP00000288840.5	O43541-1
	SMAD6	ENST00000557916.5	TSL:1	n.120C>T		non_coding_transcript_exon	Exon 1 of 5	ENSP00000452955.1	O43541-4
	SMAD6	ENST00000966143.1		c.120C>T	p.Gly40Gly	synonymous	Exon 1 of 3	ENSP00000636202.1

Frequencies

GnomAD3 genomes AF: 0.0295 AC: 4482 AN: 151856 Hom.: 91 Cov.: 32

Gnomad AFR AF: 0.00718

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0224

Gnomad ASJ AF: 0.0588

Gnomad EAS AF: 0.000583

Gnomad SAS AF: 0.00662

Gnomad FIN AF: 0.0535

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.0436

Gnomad OTH AF: 0.0316

GnomAD2 exomes AF: 0.0364 AC: 2487 AN: 68238 AF XY: 0.0353

Gnomad AFR exome AF: 0.00627

Gnomad AMR exome AF: 0.0222

Gnomad ASJ exome AF: 0.0734

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0505

Gnomad NFE exome AF: 0.0462

Gnomad OTH exome AF: 0.0377

GnomAD4 exome AF: 0.0371 AC: 48392 AN: 1303030 Hom.: 1063 Cov.: 32 AF XY: 0.0369 AC XY: 23639 AN XY: 640752

African (AFR) AF: 0.00445 AC: 115 AN: 25830

American (AMR) AF: 0.0237 AC: 534 AN: 22508

Ashkenazi Jewish (ASJ) AF: 0.0670 AC: 1440 AN: 21494

East Asian (EAS) AF: 0.0000712 AC: 2 AN: 28104

South Asian (SAS) AF: 0.00735 AC: 493 AN: 67108

European-Finnish (FIN) AF: 0.0488 AC: 2235 AN: 45780

Middle Eastern (MID) AF: 0.0326 AC: 123 AN: 3774

European-Non Finnish (NFE) AF: 0.0403 AC: 41729 AN: 1035218

Other (OTH) AF: 0.0323 AC: 1721 AN: 53214

GnomAD4 genome AF: 0.0295 AC: 4479 AN: 151964 Hom.: 91 Cov.: 32 AF XY: 0.0295 AC XY: 2189 AN XY: 74290

African (AFR) AF: 0.00716 AC: 297 AN: 41476

American (AMR) AF: 0.0223 AC: 341 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0588 AC: 204 AN: 3470

East Asian (EAS) AF: 0.000585 AC: 3 AN: 5126

South Asian (SAS) AF: 0.00663 AC: 32 AN: 4828

European-Finnish (FIN) AF: 0.0535 AC: 565 AN: 10568

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.0436 AC: 2961 AN: 67898

Other (OTH) AF: 0.0313 AC: 66 AN: 2108

Alfa AF: 0.0203 Hom.: 20

Bravo AF: 0.0271

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Aortic valve disease 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	13
DANN	Uncertain	0.98
PhyloP100		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs149612008; hg19: chr15-66995716;