Genetic Variant SMAD5:c.1254+109C>G (chr5-136174741-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_005903.7(SMAD5):c.1254+109C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0926 in 714,996 control chromosomes in the GnomAD database, including 3,941 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 0.095 ( 824 hom., cov: 32)

Exomes 𝑓: 0.092 ( 3117 hom. )

Consequence

SMAD5
NM_005903.7 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.16

Publications

7 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.258 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	UniProt
SMAD5	NM_005903.7	MANE Select	c.1254+109C>G	intron	N/A	NP_005894.3
SMAD5	NM_001001419.3		c.1254+109C>G	intron	N/A	NP_001001419.1	Q99717
SMAD5	NM_001001420.3		c.1254+109C>G	intron	N/A	NP_001001420.1	Q99717

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SMAD5	ENST00000545279.6	TSL:1 MANE Select	c.1254+109C>G	intron	N/A	ENSP00000441954.2	Q99717
SMAD5	ENST00000509297.6	TSL:1	c.1254+109C>G	intron	N/A	ENSP00000426696.2	Q99717
SMAD5	ENST00000545620.5	TSL:5	c.1254+109C>G	intron	N/A	ENSP00000446474.2	Q99717

Frequencies

GnomAD3 genomes

AF:

0.0952

AC:

14455

AN:

151842

Hom.:

824

Cov.:

show subpopulations

Gnomad AFR

AF:

0.101

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.0956

Gnomad ASJ

AF:

0.0576

Gnomad EAS

AF:

0.270

Gnomad SAS

AF:

0.0814

Gnomad FIN

AF:

0.138

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.0754

Gnomad OTH

AF:

0.101

GnomAD4 exome

AF:

0.0919

AC:

51723

AN:

563036

Hom.:

3117

AF XY:

0.0904

AC XY:

26605

AN XY:

294424

show subpopulations

African (AFR)

AF:

0.104

AC:

1530

AN:

14714

American (AMR)

AF:

0.113

AC:

2858

AN:

25374

Ashkenazi Jewish (ASJ)

AF:

0.0620

AC:

911

AN:

14692

East Asian (EAS)

AF:

0.260

AC:

8776

AN:

33720

South Asian (SAS)

AF:

0.0766

AC:

3490

AN:

45574

European-Finnish (FIN)

AF:

0.130

AC:

5035

AN:

38722

Middle Eastern (MID)

AF:

0.103

AC:

237

AN:

2296

European-Non Finnish (NFE)

AF:

0.0730

AC:

26160

AN:

358474

Other (OTH)

AF:

0.0925

AC:

2726

AN:

29470

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

2272

4545

6817

9090

11362

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

540

1080

1620

2160

2700

<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:

0.0952

AC:

14473

AN:

151960

Hom.:

824

Cov.:

AF XY:

0.0990

AC XY:

7351

AN XY:

74258

show subpopulations

African (AFR)

AF:

0.101

AC:

4181

AN:

41446

American (AMR)

AF:

0.0955

AC:

1457

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.0576

AC:

200

AN:

3470

East Asian (EAS)

AF:

0.270

AC:

1400

AN:

5182

South Asian (SAS)

AF:

0.0806

AC:

388

AN:

4812

European-Finnish (FIN)

AF:

0.138

AC:

1450

AN:

10516

Middle Eastern (MID)

AF:

0.0952

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0754

AC:

5124

AN:

67966

Other (OTH)

AF:

0.106

AC:

223

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

664

1328

1991

2655

3319

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

170

340

510

680

850

<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:

0.0372

Hom.:

Bravo

AF:

0.0961

Asia WGS

AF:

0.204

AC:

712

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

2.5

(source)

DANN

Benign

0.60

PhyloP100

-1.2

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