15-66781042-G-T

Variant names:

• chr15-66781042-G-T
• NM_005585.5:c.998G>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_005585.5(SMAD6):​c.998G>T​(p.Ser333Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,448,228 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. S333T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SMAD6 NM_005585.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.44

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 4 ACMG points.

• PM1: In a domain MH2 (size 165) in uniprot entity SMAD6_HUMAN there are 9 pathogenic changes around while only 3 benign (75%) in NM_005585.5
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD6	NM_005585.5	c.998G>T	p.Ser333Ile	missense_variant	Exon 4 of 4	ENST00000288840.10	NP_005576.3
SMAD6	XM_011521561.3	c.215G>T	p.Ser72Ile	missense_variant	Exon 4 of 4		XP_011519863.1
SMAD6	NR_027654.2	n.2153G>T		non_coding_transcript_exon_variant	Exon 5 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD6	ENST00000288840.10	c.998G>T	p.Ser333Ile	missense_variant	Exon 4 of 4	1	NM_005585.5	ENSP00000288840.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1448228 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 720434

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000226

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	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.7	M
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.5	N
REVEL	Pathogenic	0.76
Sift	Benign	0.10	T
Sift4G	Benign	0.20	T
Polyphen		0.86	P
Vest4		0.41
MutPred		0.67		Loss of disorder (P = 0.0272);
MVP		0.89
MPC		0.83
ClinPred		0.98	D
GERP RS		4.6
Varity_R		0.34
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: chr15-67073380;