NM_005585.5:c.61G>C

Variant names:

• chr15-66703319-G-C
• rs188799901
• NM_005585.5:c.61G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_005585.5(SMAD6):​c.61G>C​(p.Asp21His) variant causes a missense change. The variant allele was found at a frequency of 0.000003 in 1,335,408 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D21N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: SMAD6 NM_005585.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.16
• 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 4 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 20 uncertain in NM_005585.5
• PM2: Very rare variant in population databases, with high coverage

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.61G>C	p.Asp21His	missense	Exon 1 of 4	NP_005576.3
	SMAD6	NR_027654.2		n.1084G>C		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.61G>C	p.Asp21His	missense	Exon 1 of 4	ENSP00000288840.5	O43541-1
	SMAD6	ENST00000557916.5	TSL:1	n.61G>C		non_coding_transcript_exon	Exon 1 of 5	ENSP00000452955.1	O43541-4
	SMAD6	ENST00000966143.1		c.61G>C	p.Asp21His	missense	Exon 1 of 3	ENSP00000636202.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000300 AC: 4 AN: 1335408 Hom.: 0 Cov.: 31 AF XY: 0.00000304 AC XY: 2 AN XY: 658918

African (AFR) AF: 0.00 AC: 0 AN: 26972

American (AMR) AF: 0.00 AC: 0 AN: 27392

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23374

East Asian (EAS) AF: 0.00 AC: 0 AN: 28650

South Asian (SAS) AF: 0.00 AC: 0 AN: 73128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47184

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4300

European-Non Finnish (NFE) AF: 0.00000286 AC: 3 AN: 1049710

Other (OTH) AF: 0.0000183 AC: 1 AN: 54698

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.59	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.7	L
PhyloP100		4.2
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-0.93	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.036	D
Polyphen		0.99	D
Vest4		0.33
MutPred		0.30		Loss of sheet (P = 0.0457)
MVP		0.81
MPC		2.5
ClinPred		0.94	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.29
gMVP		0.46
Mutation Taster		=68/32	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: rs188799901; hg19: chr15-66995657;