dbSNP rs6596284: SMAD5:c.-245+1893T>C (chr5-136134855-T-C) – 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.-245+1893T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.36 in 152,042 control chromosomes in the GnomAD database, including 10,819 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 ( 10819 hom., cov: 32)

Exomes 𝑓: 0.50 ( 0 hom. )

Consequence

SMAD5
NM_005903.7 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.651

Publications

9 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:

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=-0.9).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.532 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.-245+1893T>C	intron	N/A	NP_005894.3
SMAD5	NM_001001419.3		c.-329+1893T>C	intron	N/A	NP_001001419.1	Q99717
SMAD5	NM_001001420.3		c.-170+1893T>C	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.-245+1893T>C	intron	N/A	ENSP00000441954.2	Q99717
SMAD5	ENST00000509297.6	TSL:1	c.-245+896T>C	intron	N/A	ENSP00000426696.2	Q99717
SMAD5	ENST00000511116.5	TSL:1	c.-329+1893T>C	intron	N/A	ENSP00000424279.1	D6RBB4

Frequencies

GnomAD3 genomes

AF:

0.360

AC:

54654

AN:

151918

Hom.:

10789

Cov.:

show subpopulations

Gnomad AFR

AF:

0.538

Gnomad AMI

AF:

0.184

Gnomad AMR

AF:

0.285

Gnomad ASJ

AF:

0.343

Gnomad EAS

AF:

0.375

Gnomad SAS

AF:

0.187

Gnomad FIN

AF:

0.301

Gnomad MID

AF:

0.357

Gnomad NFE

AF:

0.291

Gnomad OTH

AF:

0.383

GnomAD4 exome

AF:

0.500

AC:

AN:

Hom.:

Cov.:

AF XY:

0.500

AC XY:

AN XY:

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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:

0.500

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.360

AC:

54731

AN:

152038

Hom.:

10819

Cov.:

AF XY:

0.356

AC XY:

26420

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.538

AC:

22296

AN:

41422

American (AMR)

AF:

0.284

AC:

4339

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.343

AC:

1190

AN:

3470

East Asian (EAS)

AF:

0.376

AC:

1948

AN:

5180

South Asian (SAS)

AF:

0.187

AC:

900

AN:

4824

European-Finnish (FIN)

AF:

0.301

AC:

3182

AN:

10582

Middle Eastern (MID)

AF:

0.363

AC:

106

AN:

292

European-Non Finnish (NFE)

AF:

0.291

AC:

19791

AN:

67968

Other (OTH)

AF:

0.384

AC:

811

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1702

3405

5107

6810

8512

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:

0.334

Hom.:

1560

Bravo

AF:

0.374

Asia WGS

AF:

0.344

AC:

1198

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

2.2

(source)

DANN

Benign

0.45

PhyloP100

-0.65

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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