rs1397296874

Variant names:

• chr15-66703616-G-A
• rs1397296874
• NM_005585.5:c.358G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-66703616-G-A
• chr15-66703616-G-C
• chr15-66703616-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005585.5(SMAD6):​c.358G>A​(p.Asp120Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000406 in 1,230,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D120E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: SMAD6 NM_005585.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.75
• 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):

• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26928172).

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.358G>A	p.Asp120Asn	missense	Exon 1 of 4	NP_005576.3
	SMAD6	NR_027654.2		n.1381G>A		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.358G>A	p.Asp120Asn	missense	Exon 1 of 4	ENSP00000288840.5	O43541-1
	SMAD6	ENST00000557916.5	TSL:1	n.358G>A		non_coding_transcript_exon	Exon 1 of 5	ENSP00000452955.1	O43541-4
	SMAD6	ENST00000966143.1		c.358G>A	p.Asp120Asn	missense	Exon 1 of 3	ENSP00000636202.1

Frequencies

GnomAD3 genomes AF: 0.00000662 AC: 1 AN: 151008 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000371 AC: 4 AN: 1079050 Hom.: 0 Cov.: 31 AF XY: 0.00000585 AC XY: 3 AN XY: 512696

African (AFR) AF: 0.00 AC: 0 AN: 22170

American (AMR) AF: 0.00 AC: 0 AN: 7986

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13168

East Asian (EAS) AF: 0.00 AC: 0 AN: 25016

South Asian (SAS) AF: 0.00 AC: 0 AN: 19790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2852

European-Non Finnish (NFE) AF: 0.00000327 AC: 3 AN: 916262

Other (OTH) AF: 0.0000236 AC: 1 AN: 42390

GnomAD4 genome AF: 0.00000662 AC: 1 AN: 151008 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73742

African (AFR) AF: 0.00 AC: 0 AN: 41326

American (AMR) AF: 0.00 AC: 0 AN: 15176

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67622

Other (OTH) AF: 0.00 AC: 0 AN: 2072

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Aortic valve disease 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	0.10
Eigen_PC	Benign	0.081
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.70	T
M_CAP	Pathogenic	0.82	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.8
PrimateAI	Pathogenic	0.97	D
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.27
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.034	D
Polyphen		0.97	D
Vest4		0.12
MutPred		0.10		Loss of phosphorylation at S119 (P = 0.1228)
MVP		0.75
MPC		1.9
ClinPred		0.84	D
GERP RS		2.9
Varity_R		0.12
gMVP		0.38
Mutation Taster		=89/11	polymorphism

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: rs1397296874; hg19: chr15-66995954;