rs148705603

Positions:

• chr15-66781000-C-G
• chr15-66781000-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005585.5(SMAD6):​c.956C>G​(p.Ala319Gly) variant causes a missense change. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A319V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMAD6 NM_005585.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.06

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34860754).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD6	NM_005585.5	c.956C>G	p.Ala319Gly	missense_variant	4/4	ENST00000288840.10
SMAD6	XM_011521561.3	c.173C>G	p.Ala58Gly	missense_variant	4/4
SMAD6	NR_027654.2	n.2111C>G		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD6	ENST00000288840.10	c.956C>G	p.Ala319Gly	missense_variant	4/4	1	NM_005585.5	P1
SMAD6	ENST00000557916.5	c.*71C>G		3_prime_UTR_variant, NMD_transcript_variant	5/5	1
SMAD6	ENST00000559931.5	c.*71C>G		3_prime_UTR_variant, NMD_transcript_variant	4/4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.35	T
MetaSVM	Uncertain	0.79	D
MutationAssessor	Benign	1.9	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.50
Sift	Benign	0.11	T
Sift4G	Uncertain	0.052	T
Polyphen		0.96	D
Vest4		0.26
MutPred		0.23		Gain of relative solvent accessibility (P = 0.1571);
MVP		0.91
MPC		0.29
ClinPred		0.86	D
GERP RS		5.6
Varity_R		0.15
gMVP		0.29

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: rs148705603; hg19: chr15-67073338;