15-66703262-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_005585.5(SMAD6):ā€‹c.4T>Gā€‹(p.Phe2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000076 in 1,316,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 7.6e-7 ( 0 hom. )

Consequence

SMAD6
NM_005585.5 missense

Scores

6
9
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.94
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 Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.846

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SMAD6NM_005585.5 linkuse as main transcriptc.4T>G p.Phe2Val missense_variant 1/4 ENST00000288840.10 NP_005576.3
SMAD6NR_027654.2 linkuse as main transcriptn.1027T>G non_coding_transcript_exon_variant 1/5
SMAD6XR_931827.3 linkuse as main transcriptn.1027T>G non_coding_transcript_exon_variant 1/4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SMAD6ENST00000288840.10 linkuse as main transcriptc.4T>G p.Phe2Val missense_variant 1/41 NM_005585.5 ENSP00000288840 P1O43541-1
SMAD6ENST00000557916.5 linkuse as main transcriptc.4T>G p.Phe2Val missense_variant, NMD_transcript_variant 1/51 ENSP00000452955 O43541-4
SMAD6ENST00000612349.1 linkuse as main transcriptn.186T>G non_coding_transcript_exon_variant 1/1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
7.60e-7
AC:
1
AN:
1316530
Hom.:
0
Cov.:
31
AF XY:
0.00000154
AC XY:
1
AN XY:
650142
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:
9.61e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 17, 2023The c.4T>G (p.F2V) alteration is located in exon 1 (coding exon 1) of the SMAD6 gene. This alteration results from a T to G substitution at nucleotide position 4, causing the phenylalanine (F) at amino acid position 2 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Uncertain
-0.070
CADD
Pathogenic
27
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.76
D
Eigen
Uncertain
0.39
Eigen_PC
Uncertain
0.36
FATHMM_MKL
Benign
0.65
D
LIST_S2
Benign
0.57
T
M_CAP
Pathogenic
0.81
D
MetaRNN
Pathogenic
0.85
D
MetaSVM
Uncertain
-0.14
T
MutationAssessor
Benign
1.9
L
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.94
D
PROVEAN
Uncertain
-2.4
N
REVEL
Uncertain
0.53
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.59
MutPred
0.37
Gain of methylation at K5 (P = 0.097);
MVP
0.80
MPC
2.6
ClinPred
0.95
D
GERP RS
3.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.54
gMVP
0.46

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: chr15-66995600; API