chr15-66716485-G-T

Variant names:

• chr15-66716485-G-T
• rs144403747
• NM_005585.5:c.939G>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_005585.5(SMAD6):​c.939G>T​(p.Pro313Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P313P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMAD6 NM_005585.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0520
• Publications: 0 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP7: Synonymous conserved (PhyloP=-0.052 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD6	NM_005585.5	c.939G>T	p.Pro313Pro	synonymous_variant	Exon 3 of 4	ENST00000288840.10	NP_005576.3
SMAD6	XM_011521561.3	c.156G>T	p.Pro52Pro	synonymous_variant	Exon 3 of 4		XP_011519863.1
SMAD6	NR_027654.2	n.1962G>T		non_coding_transcript_exon_variant	Exon 3 of 5
SMAD6	XR_931827.3	n.*29G>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD6	ENST00000288840.10	c.939G>T	p.Pro313Pro	synonymous_variant	Exon 3 of 4	1	NM_005585.5	ENSP00000288840.5
SMAD6	ENST00000557916.5	n.939G>T		non_coding_transcript_exon_variant	Exon 3 of 5	1		ENSP00000452955.1
SMAD6	ENST00000558937.1	c.93G>T	p.Pro31Pro	synonymous_variant	Exon 2 of 3	5		ENSP00000452694.1
SMAD6	ENST00000559931.5	n.114G>T		non_coding_transcript_exon_variant	Exon 2 of 4	3		ENSP00000453446.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	6.1
DANN	Benign	0.75
PhyloP100		-0.052
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs144403747; hg19: chr15-67008823;