chr15-66703215-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_005585.5(SMAD6):​c.-44C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0196 in 1,318,380 control chromosomes in the GnomAD database, including 333 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 19 hom., cov: 33)
Exomes 𝑓: 0.020 ( 314 hom. )

Consequence

SMAD6
NM_005585.5 5_prime_UTR

Scores

1
1

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.18
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 Benign. Variant got -18 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.35).
BP6
Variant 15-66703215-C-T is Benign according to our data. Variant chr15-66703215-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1208555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-66703215-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0148 (2255/152178) while in subpopulation NFE AF= 0.0227 (1541/67974). AF 95% confidence interval is 0.0217. There are 19 homozygotes in gnomad4. There are 1015 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 2255 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SMAD6NM_005585.5 linkuse as main transcriptc.-44C>T 5_prime_UTR_variant 1/4 ENST00000288840.10 NP_005576.3
SMAD6NR_027654.2 linkuse as main transcriptn.980C>T non_coding_transcript_exon_variant 1/5
SMAD6XR_931827.3 linkuse as main transcriptn.980C>T 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.-44C>T 5_prime_UTR_variant 1/41 NM_005585.5 ENSP00000288840 P1O43541-1
SMAD6ENST00000612349.1 linkuse as main transcriptn.139C>T non_coding_transcript_exon_variant 1/1
SMAD6ENST00000557916.5 linkuse as main transcript upstream_gene_variant 1 ENSP00000452955 O43541-4

Frequencies

GnomAD3 genomes
AF:
0.0148
AC:
2256
AN:
152070
Hom.:
19
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00437
Gnomad AMI
AF:
0.00439
Gnomad AMR
AF:
0.0178
Gnomad ASJ
AF:
0.0438
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00145
Gnomad FIN
AF:
0.00538
Gnomad MID
AF:
0.00955
Gnomad NFE
AF:
0.0227
Gnomad OTH
AF:
0.0191
GnomAD3 exomes
AF:
0.0159
AC:
541
AN:
34100
Hom.:
14
AF XY:
0.0150
AC XY:
275
AN XY:
18354
show subpopulations
Gnomad AFR exome
AF:
0.00659
Gnomad AMR exome
AF:
0.0119
Gnomad ASJ exome
AF:
0.0496
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00282
Gnomad FIN exome
AF:
0.00731
Gnomad NFE exome
AF:
0.0233
Gnomad OTH exome
AF:
0.0248
GnomAD4 exome
AF:
0.0203
AC:
23628
AN:
1166202
Hom.:
314
Cov.:
21
AF XY:
0.0197
AC XY:
11152
AN XY:
565456
show subpopulations
Gnomad4 AFR exome
AF:
0.00264
Gnomad4 AMR exome
AF:
0.0146
Gnomad4 ASJ exome
AF:
0.0437
Gnomad4 EAS exome
AF:
0.0000371
Gnomad4 SAS exome
AF:
0.00169
Gnomad4 FIN exome
AF:
0.00839
Gnomad4 NFE exome
AF:
0.0223
Gnomad4 OTH exome
AF:
0.0204
GnomAD4 genome
AF:
0.0148
AC:
2255
AN:
152178
Hom.:
19
Cov.:
33
AF XY:
0.0136
AC XY:
1015
AN XY:
74412
show subpopulations
Gnomad4 AFR
AF:
0.00436
Gnomad4 AMR
AF:
0.0177
Gnomad4 ASJ
AF:
0.0438
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00145
Gnomad4 FIN
AF:
0.00538
Gnomad4 NFE
AF:
0.0227
Gnomad4 OTH
AF:
0.0189
Alfa
AF:
0.0162
Hom.:
2
Bravo
AF:
0.0153
Asia WGS
AF:
0.00145
AC:
5
AN:
3470

ClinVar

Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Likely benign, criteria provided, single submitterclinical testingGeneDxJul 29, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.35
CADD
Benign
19
DANN
Uncertain
0.98

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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: rs138443554; hg19: chr15-66995553; API