Genetic Variant SEPSECS:c.115-5_115-4dupTT (chr4-25159110-T-TAA) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BS1

The NM_016955.4(SEPSECS):c.115-5_115-4dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0266 in 1,419,864 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00096 ( 0 hom., cov: 26)

Exomes 𝑓: 0.029 ( 0 hom. )

Consequence

SEPSECS
NM_016955.4 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.42

Publications

5 publications found

Variant links:

Genes affected

SEPSECS (HGNC:30605): (Sep (O-phosphoserine) tRNA:Sec (selenocysteine) tRNA synthase) The amino acid selenocysteine is the only amino acid that does not have its own tRNA synthetase. Instead, this amino acid is synthesized on its cognate tRNA in a three step process. The protein encoded by this gene catalyzes the third step in the process, the conversion of O-phosphoseryl-tRNA(Sec) to selenocysteinyl-tRNA(Sec).[provided by RefSeq, Mar 2011]

SEPSECS Gene-Disease associations (from GenCC):

pontocerebellar hypoplasia type 2D
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Broad Center for Mendelian Genomics, PanelApp Australia, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
pontocerebellar hypoplasia type 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
progressive cerebello-cerebral atrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SEPSECS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Variant has high frequency in the AFR (0.0594) population. However there is too low homozygotes in high coverage region: (expected more than 250, got 0).

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000956 (135/141172) while in subpopulation EAS AF = 0.00305 (15/4918). AF 95% confidence interval is 0.00188. There are 0 homozygotes in GnomAd4. There are 65 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEPSECS	NM_016955.4 link	c.115-5_115-4dupTT		splice_region_variant, intron_variant	Intron 1 of 10	ENST00000382103.7	NP_058651.3	Q9HD40-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEPSECS	ENST00000382103.7 link	c.115-5_115-4dupTT		splice_region_variant, intron_variant	Intron 1 of 10	1	NM_016955.4	ENSP00000371535.2		Q9HD40-1

Frequencies

GnomAD3 genomes

AF:

0.000907

AC:

128

AN:

141090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00154

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000284

Gnomad ASJ

AF:

0.000299

Gnomad EAS

AF:

0.00304

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00120

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000531

Gnomad OTH

AF:

0.00208

GnomAD2 exomes

AF:

0.0341

AC:

4382

AN:

128440

AF XY:

0.0346

show subpopulations

Gnomad AFR exome

AF:

0.0619

Gnomad AMR exome

AF:

0.0370

Gnomad ASJ exome

AF:

0.0393

Gnomad EAS exome

AF:

0.0466

Gnomad FIN exome

AF:

0.0165

Gnomad NFE exome

AF:

0.0291

Gnomad OTH exome

AF:

0.0361

GnomAD4 exome

AF:

0.0294

AC:

37592

AN:

1278692

Hom.:

Cov.:

AF XY:

0.0293

AC XY:

18605

AN XY:

635790

show subpopulations

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

African (AFR)

AF:

0.0618

AC:

1672

AN:

27044

American (AMR)

AF:

0.0281

AC:

806

AN:

28650

Ashkenazi Jewish (ASJ)

AF:

0.0304

AC:

685

AN:

22500

East Asian (EAS)

AF:

0.0259

AC:

933

AN:

35980

South Asian (SAS)

AF:

0.0356

AC:

2484

AN:

69686

European-Finnish (FIN)

AF:

0.0127

AC:

596

AN:

46972

Middle Eastern (MID)

AF:

0.0221

AC:

114

AN:

5168

European-Non Finnish (NFE)

AF:

0.0289

AC:

28604

AN:

989556

Other (OTH)

AF:

0.0320

AC:

1698

AN:

53136

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.290

Heterozygous variant carriers

2837

5673

8510

11346

14183

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

1166

2332

3498

4664

5830

<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:

0.000956

AC:

135

AN:

141172

Hom.:

Cov.:

AF XY:

0.000950

AC XY:

AN XY:

68406

show subpopulations

African (AFR)

AF:

0.00169

AC:

AN:

38998

American (AMR)

AF:

0.000284

AC:

AN:

14074

Ashkenazi Jewish (ASJ)

AF:

0.000299

AC:

AN:

3340

East Asian (EAS)

AF:

0.00305

AC:

AN:

4918

South Asian (SAS)

AF:

0.000227

AC:

AN:

4410

European-Finnish (FIN)

AF:

0.00120

AC:

AN:

8360

Middle Eastern (MID)

AF:

0.00

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.000531

AC:

AN:

63976

Other (OTH)

AF:

0.00206

AC:

AN:

1942

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.414

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000840

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-2.4

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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4-25159110-TAAAAA-TAAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over