rs748622672

Positions:

• chr15-66703740-C-G
• chr15-66703740-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005585.5(SMAD6):​c.482C>G​(p.Ala161Gly) variant causes a missense 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. 13/21 in silico tools predict a benign outcome for this variant. 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. A161V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMAD6 NM_005585.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.26

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24729496).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD6	NM_005585.5	c.482C>G	p.Ala161Gly	missense_variant	1/4	ENST00000288840.10
SMAD6	NR_027654.2	n.1505C>G		non_coding_transcript_exon_variant	1/5
SMAD6	XR_931827.3	n.1505C>G		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD6	ENST00000288840.10	c.482C>G	p.Ala161Gly	missense_variant	1/4	1	NM_005585.5	P1
SMAD6	ENST00000557916.5	c.482C>G	p.Ala161Gly	missense_variant, NMD_transcript_variant	1/5	1
SMAD6	ENST00000612349.1	n.664C>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.48	T
M_CAP	Pathogenic	0.88	D
MetaRNN	Benign	0.25	T
MetaSVM	Uncertain	-0.089	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	0.58	N;N
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.15
Sift	Benign	0.19	T
Sift4G	Benign	0.26	T
Polyphen		0.0	B
Vest4		0.098
MutPred		0.26		Loss of helix (P = 0.0196);
MVP		0.72
MPC		1.1
ClinPred		0.20	T
GERP RS		2.2
Varity_R		0.085
gMVP		0.23

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

LitVar

Other links and lift over

dbSNP: rs748622672; hg19: chr15-66996078;