Genetic Variant GSDMB:c.-15+269G>A (chr17-39918265-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 NM_001388420.1(GSDMB):c.-949G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.524 in 151,876 control chromosomes in the GnomAD database, including 21,058 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 0.52 ( 21055 hom., cov: 31)

Exomes 𝑓: 0.56 ( 3 hom. )

Consequence

GSDMB
NM_001388420.1 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.89

Publications

38 publications found

Variant links:

Genes affected

GSDMB (HGNC:23690): (gasdermin B) This gene encodes a member of the gasdermin-domain containing protein family. Other gasdermin-family genes are implicated in the regulation of apoptosis in epithelial cells, and are linked to cancer. Alternative splicing and the use of alternative promoters results in multiple transcript variants. Additional variants have been described, but they are candidates for nonsense-mediated mRNA decay (NMD) and are unlikely to be protein-coding. [provided by RefSeq, Nov 2016]

GSDMB 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=-0.57).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.709 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001388420.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
GSDMB	NM_001165958.2	MANE Select	c.-15+269G>A	intron	N/A	NP_001159430.1
GSDMB	NM_001388420.1		c.-949G>A	5_prime_UTR	Exon 1 of 10	NP_001375349.1
GSDMB	NM_001388421.1		c.-949G>A	5_prime_UTR	Exon 1 of 9	NP_001375350.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
GSDMB	ENST00000418519.6	TSL:5 MANE Select	c.-15+269G>A	intron	N/A	ENSP00000415049.1
GSDMB	ENST00000901434.1		c.-949G>A	5_prime_UTR	Exon 1 of 9	ENSP00000571493.1
GSDMB	ENST00000520542.5	TSL:2	c.-6+269G>A	intron	N/A	ENSP00000430157.1

Frequencies

GnomAD3 genomes

AF:

0.524

AC:

79574

AN:

151742

Hom.:

21055

Cov.:

show subpopulations

Gnomad AFR

AF:

0.549

Gnomad AMI

AF:

0.327

Gnomad AMR

AF:

0.557

Gnomad ASJ

AF:

0.522

Gnomad EAS

AF:

0.728

Gnomad SAS

AF:

0.570

Gnomad FIN

AF:

0.437

Gnomad MID

AF:

0.535

Gnomad NFE

AF:

0.500

Gnomad OTH

AF:

0.533

GnomAD4 exome

AF:

0.563

AC:

AN:

Hom.:

Cov.:

AF XY:

0.375

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:

0.667

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.625

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0338994), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.392

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:

0.524

AC:

79590

AN:

151860

Hom.:

21055

Cov.:

AF XY:

0.525

AC XY:

38942

AN XY:

74230

show subpopulations

African (AFR)

AF:

0.548

AC:

22679

AN:

41396

American (AMR)

AF:

0.556

AC:

8502

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.522

AC:

1813

AN:

3472

East Asian (EAS)

AF:

0.728

AC:

3752

AN:

5152

South Asian (SAS)

AF:

0.570

AC:

2741

AN:

4812

European-Finnish (FIN)

AF:

0.437

AC:

4601

AN:

10540

Middle Eastern (MID)

AF:

0.537

AC:

158

AN:

294

European-Non Finnish (NFE)

AF:

0.500

AC:

33919

AN:

67890

Other (OTH)

AF:

0.534

AC:

1127

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1948

3896

5843

7791

9739

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

710

1420

2130

2840

3550

<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:

0.511

Hom.:

25491

Bravo

AF:

0.541

Asia WGS

AF:

0.583

AC:

2029

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

7.5

(source)

DANN

Benign

0.90

PhyloP100

-1.9

PromoterAI

-0.026

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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