Genetic Variant SEPSECS:c.115-6_115-4dupTTT (chr4-25159110-T-TAAA) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_016955.4(SEPSECS):c.115-6_115-4dupTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,456,988 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 0.0000071 ( 0 hom., cov: 26)

Exomes 𝑓: 0.0015 ( 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEPSECS	NM_016955.4 link	c.115-6_115-4dupTTT		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.115-6_115-4dupTTT		splice_region_variant, intron_variant	Intron 1 of 10	1	NM_016955.4	ENSP00000371535.2		Q9HD40-1

Frequencies

GnomAD3 genomes

AF:

0.00000708

AC:

AN:

141156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000119

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00191

AC:

245

AN:

128440

AF XY:

0.00183

show subpopulations

Gnomad AFR exome

AF:

0.00444

Gnomad AMR exome

AF:

0.00180

Gnomad ASJ exome

AF:

0.00177

Gnomad EAS exome

AF:

0.00413

Gnomad FIN exome

AF:

0.000486

Gnomad NFE exome

AF:

0.00159

Gnomad OTH exome

AF:

0.00128

GnomAD4 exome

AF:

0.00154

AC:

2027

AN:

1315832

Hom.:

Cov.:

AF XY:

0.00149

AC XY:

972

AN XY:

654292

show subpopulations

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

African (AFR)

AF:

0.00329

AC:

AN:

27694

American (AMR)

AF:

0.00132

AC:

AN:

29442

Ashkenazi Jewish (ASJ)

AF:

0.00152

AC:

AN:

23084

East Asian (EAS)

AF:

0.00154

AC:

AN:

36928

South Asian (SAS)

AF:

0.00209

AC:

150

AN:

71916

European-Finnish (FIN)

AF:

0.000416

AC:

AN:

48048

Middle Eastern (MID)

AF:

0.000572

AC:

AN:

5244

European-Non Finnish (NFE)

AF:

0.00152

AC:

1551

AN:

1018950

Other (OTH)

AF:

0.00149

AC:

AN:

54526

⚠️ 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: 0.257

Heterozygous variant carriers

246

493

739

986

1232

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

136

204

272

340

<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:

0.00000708

AC:

AN:

141156

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

68344

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

38896

American (AMR)

AF:

0.00

AC:

AN:

14066

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3340

East Asian (EAS)

AF:

0.00

AC:

AN:

4930

South Asian (SAS)

AF:

0.00

AC:

AN:

4426

European-Finnish (FIN)

AF:

0.000119

AC:

AN:

8390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

64008

Other (OTH)

AF:

0.00

AC:

AN:

1922

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over