rs199822239

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The ENST00000288840.10(SMAD6):​c.973G>A​(p.Ala325Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000231 in 1,580,110 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00024 ( 1 hom. )

Consequence

SMAD6
ENST00000288840.10 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 5.77
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.08999571).
BS2
High AC in GnomAd4 at 22 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SMAD6NM_005585.5 linkuse as main transcriptc.973G>A p.Ala325Thr missense_variant 4/4 ENST00000288840.10 NP_005576.3
SMAD6XM_011521561.3 linkuse as main transcriptc.190G>A p.Ala64Thr missense_variant 4/4 XP_011519863.1
SMAD6NR_027654.2 linkuse as main transcriptn.2128G>A non_coding_transcript_exon_variant 5/5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SMAD6ENST00000288840.10 linkuse as main transcriptc.973G>A p.Ala325Thr missense_variant 4/41 NM_005585.5 ENSP00000288840 P1O43541-1
SMAD6ENST00000557916.5 linkuse as main transcriptc.*88G>A 3_prime_UTR_variant, NMD_transcript_variant 5/51 ENSP00000452955 O43541-4
SMAD6ENST00000559931.5 linkuse as main transcriptc.*88G>A 3_prime_UTR_variant, NMD_transcript_variant 4/43 ENSP00000453446

Frequencies

GnomAD3 genomes
AF:
0.000145
AC:
22
AN:
152176
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.000576
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000250
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.000131
AC:
27
AN:
205972
Hom.:
0
AF XY:
0.000132
AC XY:
15
AN XY:
113636
show subpopulations
Gnomad AFR exome
AF:
0.0000806
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000213
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000257
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000240
AC:
343
AN:
1427934
Hom.:
1
Cov.:
34
AF XY:
0.000234
AC XY:
166
AN XY:
708366
show subpopulations
Gnomad4 AFR exome
AF:
0.000367
Gnomad4 AMR exome
AF:
0.0000468
Gnomad4 ASJ exome
AF:
0.000155
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000281
Gnomad4 OTH exome
AF:
0.000253
GnomAD4 genome
AF:
0.000145
AC:
22
AN:
152176
Hom.:
0
Cov.:
32
AF XY:
0.000135
AC XY:
10
AN XY:
74332
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.000576
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000250
Gnomad4 OTH
AF:
0.000479
Alfa
AF:
0.000365
Hom.:
0
Bravo
AF:
0.000181
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000149
AC:
18

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

SMAD6-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesSep 24, 2023The SMAD6 c.973G>A variant is predicted to result in the amino acid substitution p.Ala325Thr. This variant was reported in an individual with congenital mitral regurgitation (Tan et al. 2012. PubMed ID: 22275001). Functional studies showed that this variant does not significantly affect protein function (Tan et al. 2012. PubMed ID: 22275001; Calpena et al. 2020. PubMed ID: 32499606). This variant is reported in 0.027% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-67073355-G-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Aortic valve disease 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 19, 2024This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 325 of the SMAD6 protein (p.Ala325Thr). This variant is present in population databases (rs199822239, gnomAD 0.03%). This missense change has been observed in individual(s) with congenital cardiovascular malformation (PMID: 22275001). ClinVar contains an entry for this variant (Variation ID: 405517). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SMAD6 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect SMAD6 function (PMID: 22275001, 32499606). 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. -
Craniosynostosis 7 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert EinsteinNov 30, 2021ACMG classification criteria: BP4 supporting -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxSep 02, 2023In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with congenital mitral regurgitation (Tan et al., 2012); This variant is associated with the following publications: (PMID: 32499606, 22275001) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.068
BayesDel_addAF
Benign
-0.046
T
BayesDel_noAF
Uncertain
0.0
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.35
T
Eigen
Benign
-0.083
Eigen_PC
Benign
0.14
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Benign
0.85
T
M_CAP
Benign
0.069
D
MetaRNN
Benign
0.090
T
MetaSVM
Uncertain
0.11
D
MutationAssessor
Benign
1.3
L
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.55
T
PROVEAN
Benign
-0.74
N
REVEL
Uncertain
0.37
Sift
Benign
0.25
T
Sift4G
Benign
0.29
T
Polyphen
0.011
B
Vest4
0.11
MVP
0.82
MPC
0.25
ClinPred
0.082
T
GERP RS
4.6
Varity_R
0.083
gMVP
0.37

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: rs199822239; hg19: chr15-67073355; COSMIC: COSV56595702; API