Genetic Variant SMAD5:c.*5074G>T (chr5-136182554-G-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The NM_005903.7(SMAD5):c.*5074G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.36 in 152,478 control chromosomes in the GnomAD database, including 10,886 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 0.36 ( 10864 hom., cov: 33)

Exomes 𝑓: 0.31 ( 22 hom. )

Consequence

SMAD5
NM_005903.7 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.560

Publications

13 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.533 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005903.7. 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.*5074G>T	3_prime_UTR	Exon 8 of 8	NP_005894.3
SMAD5	NM_001001419.3		c.*5074G>T	3_prime_UTR	Exon 9 of 9	NP_001001419.1
SMAD5	NM_001001420.3		c.*5074G>T	3_prime_UTR	Exon 7 of 7	NP_001001420.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
SMAD5	ENST00000545279.6	TSL:1 MANE Select	c.*5074G>T	3_prime_UTR	Exon 8 of 8	ENSP00000441954.2
SMAD5	ENST00000545620.5	TSL:5	c.*5074G>T	3_prime_UTR	Exon 7 of 7	ENSP00000446474.2
SMAD5	ENST00000513418.1	TSL:5	n.163-4607G>T	intron	N/A	ENSP00000427650.1

Frequencies

GnomAD3 genomes

AF:

0.360

AC:

54751

AN:

151928

Hom.:

10835

Cov.:

show subpopulations

Gnomad AFR

AF:

0.538

Gnomad AMI

AF:

0.185

Gnomad AMR

AF:

0.285

Gnomad ASJ

AF:

0.343

Gnomad EAS

AF:

0.375

Gnomad SAS

AF:

0.186

Gnomad FIN

AF:

0.303

Gnomad MID

AF:

0.361

Gnomad NFE

AF:

0.292

Gnomad OTH

AF:

0.383

GnomAD4 exome

AF:

0.315

AC:

136

AN:

432

Hom.:

Cov.:

AF XY:

0.338

AC XY:

AN XY:

260

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.317

AC:

135

AN:

426

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.500

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.361

AC:

54826

AN:

152046

Hom.:

10864

Cov.:

AF XY:

0.356

AC XY:

26485

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.539

AC:

22341

AN:

41474

American (AMR)

AF:

0.284

AC:

4348

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.343

AC:

1189

AN:

3470

East Asian (EAS)

AF:

0.376

AC:

1942

AN:

5170

South Asian (SAS)

AF:

0.185

AC:

892

AN:

4822

European-Finnish (FIN)

AF:

0.303

AC:

3197

AN:

10544

Middle Eastern (MID)

AF:

0.367

AC:

108

AN:

294

European-Non Finnish (NFE)

AF:

0.292

AC:

19827

AN:

67952

Other (OTH)

AF:

0.385

AC:

814

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1738

3476

5213

6951

8689

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

508

1016

1524

2032

2540

<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:

0.289

Hom.:

2411

Bravo

AF:

0.374

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.70

PhyloP100

0.56

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over