dbSNP rs3764942: SMAD5:c.-393C>T (chr5-136133811-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000509297.6(SMAD5):c.-393C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0969 in 154,682 control chromosomes in the GnomAD database, including 869 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.097 ( 847 hom., cov: 32)

Exomes 𝑓: 0.12 ( 22 hom. )

Consequence

SMAD5
ENST00000509297.6 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.779

Publications

15 publications found

Variant links:

Genes affected

SMAD5 (HGNC:6771): (SMAD family member 5) The protein encoded by this gene is involved in the transforming growth factor beta signaling pathway that results in an inhibition of the proliferation of hematopoietic progenitor cells. The encoded protein is activated by bone morphogenetic proteins type 1 receptor kinase, and may be involved in cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

SMAD5 links:

SMAD5-AS1 (HGNC:30586): (SMAD5 antisense RNA 1) Predicted to be involved in signal transduction. [provided by Alliance of Genome Resources, Apr 2022]

SMAD5-AS1 links:

ENSG00000275646 (HGNC:):

ENSG00000275646 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.256 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000509297.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
SMAD5	NM_005903.7	MANE Select	c.-245+849C>T	intron	N/A	NP_005894.3
SMAD5	NM_001001419.3		c.-329+849C>T	intron	N/A	NP_001001419.1
SMAD5	NM_001001420.3		c.-170+849C>T	intron	N/A	NP_001001420.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
SMAD5	ENST00000509297.6	TSL:1	c.-393C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	ENSP00000426696.2
SMAD5	ENST00000509297.6	TSL:1	c.-393C>T	5_prime_UTR	Exon 1 of 8	ENSP00000426696.2
SMAD5	ENST00000545279.6	TSL:1 MANE Select	c.-245+849C>T	intron	N/A	ENSP00000441954.2

Frequencies

GnomAD3 genomes

AF:

0.0965

AC:

14657

AN:

151920

Hom.:

844

Cov.:

show subpopulations

Gnomad AFR

AF:

0.105

Gnomad AMI

AF:

0.0242

Gnomad AMR

AF:

0.0957

Gnomad ASJ

AF:

0.0577

Gnomad EAS

AF:

0.267

Gnomad SAS

AF:

0.0838

Gnomad FIN

AF:

0.137

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.0755

Gnomad OTH

AF:

0.102

GnomAD4 exome

AF:

0.116

AC:

306

AN:

2644

Hom.:

Cov.:

AF XY:

0.105

AC XY:

142

AN XY:

1358

show subpopulations

African (AFR)

AF:

0.162

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.116

AC:

AN:

European-Finnish (FIN)

AF:

0.120

AC:

AN:

558

Middle Eastern (MID)

AF:

0.122

AC:

197

AN:

1618

European-Non Finnish (NFE)

AF:

0.0238

AC:

AN:

Other (OTH)

AF:

0.0841

AC:

AN:

226

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0966

AC:

14683

AN:

152038

Hom.:

847

Cov.:

AF XY:

0.100

AC XY:

7456

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.106

AC:

4387

AN:

41494

American (AMR)

AF:

0.0956

AC:

1462

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0577

AC:

200

AN:

3468

East Asian (EAS)

AF:

0.268

AC:

1380

AN:

5152

South Asian (SAS)

AF:

0.0831

AC:

400

AN:

4816

European-Finnish (FIN)

AF:

0.137

AC:

1449

AN:

10540

Middle Eastern (MID)

AF:

0.0952

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0755

AC:

5129

AN:

67962

Other (OTH)

AF:

0.107

AC:

226

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

666

1333

1999

2666

3332

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

344

516

688

860

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0828

Hom.:

2476

Bravo

AF:

0.0975

Asia WGS

AF:

0.206

AC:

719

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.88

PhyloP100

-0.78

PromoterAI

-0.074

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over