15-66703364-G-C

Position:

• chr15-66703364-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005585.5(SMAD6):​c.106G>C​(p.Asp36His) variant causes a missense change. The variant allele was found at a frequency of 0.000000755 in 1,323,648 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: SMAD6 NM_005585.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.67

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD6	NM_005585.5	c.106G>C	p.Asp36His	missense_variant	1/4	ENST00000288840.10	NP_005576.3
SMAD6	NR_027654.2	n.1129G>C		non_coding_transcript_exon_variant	1/5
SMAD6	XR_931827.3	n.1129G>C		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD6	ENST00000288840.10	c.106G>C	p.Asp36His	missense_variant	1/4	1	NM_005585.5	ENSP00000288840.5
SMAD6	ENST00000557916.5	n.106G>C		non_coding_transcript_exon_variant	1/5	1		ENSP00000452955.1
SMAD6	ENST00000612349.1	n.288G>C		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.55e-7 AC: 1 AN: 1323648 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 652224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000353

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.53	T
M_CAP	Pathogenic	0.82	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.7	L
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-0.71	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.026	D
Polyphen		1.0	D
Vest4		0.30
MutPred		0.096		Gain of glycosylation at S41 (P = 0.1425);
MVP		0.75
MPC		1.8
ClinPred		0.84	D
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.15
gMVP		0.56

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-66995702;