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rs985309653

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM5BP4_ModerateBS2

The NM_005585.5(SMAD6):c.278T>C(p.Met93Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,221,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M93I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

SMAD6
NM_005585.5 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.794
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM5
Other missense variant is known to change same aminoacid residue: Variant chr15-66703535-A-T is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.11689383).
BS2
High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SMAD6NM_005585.5 linkuse as main transcriptc.278T>C p.Met93Thr missense_variant 1/4 ENST00000288840.10
SMAD6NR_027654.2 linkuse as main transcriptn.1301T>C non_coding_transcript_exon_variant 1/5
SMAD6XR_931827.3 linkuse as main transcriptn.1301T>C non_coding_transcript_exon_variant 1/4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SMAD6ENST00000288840.10 linkuse as main transcriptc.278T>C p.Met93Thr missense_variant 1/41 NM_005585.5 P1O43541-1
SMAD6ENST00000557916.5 linkuse as main transcriptc.278T>C p.Met93Thr missense_variant, NMD_transcript_variant 1/51 O43541-4
SMAD6ENST00000612349.1 linkuse as main transcriptn.460T>C non_coding_transcript_exon_variant 1/1

Frequencies

GnomAD3 genomes
AF:
0.0000530
AC:
8
AN:
150992
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000727
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000739
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000393
AC:
42
AN:
1070042
Hom.:
0
Cov.:
31
AF XY:
0.0000494
AC XY:
25
AN XY:
506452
show subpopulations
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:
0.00
Gnomad4 NFE exome
AF:
0.0000461
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000530
AC:
8
AN:
150992
Hom.:
0
Cov.:
33
AF XY:
0.0000136
AC XY:
1
AN XY:
73750
show subpopulations
Gnomad4 AFR
AF:
0.0000727
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000739
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000302

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 20, 2023The c.278T>C (p.M93T) alteration is located in exon 1 (coding exon 1) of the SMAD6 gene. This alteration results from a T to C substitution at nucleotide position 278, causing the methionine (M) at amino acid position 93 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJun 29, 2020Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Aortic valve disease 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeAug 23, 2022This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 93 of the SMAD6 protein (p.Met93Thr). This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with SMAD6-related conditions. ClinVar contains an entry for this variant (Variation ID: 405514). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.46
Cadd
Benign
17
Dann
Benign
0.23
DEOGEN2
Benign
0.30
T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.12
N
LIST_S2
Benign
0.27
T
M_CAP
Pathogenic
0.72
D
MetaRNN
Benign
0.12
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.1
L
MutationTaster
Benign
0.99
N;N
PrimateAI
Pathogenic
0.93
D
PROVEAN
Benign
-0.080
N
REVEL
Benign
0.091
Sift
Benign
0.66
T
Sift4G
Benign
0.47
T
Polyphen
0.0
B
Vest4
0.055
MutPred
0.28
Gain of phosphorylation at M93 (P = 4e-04);
MVP
0.31
MPC
1.3
ClinPred
0.060
T
GERP RS
2.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.19
gMVP
0.22

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs985309653; hg19: chr15-66995874; API