chr4-25159110-TA-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBA1

The NM_016955.4(SEPSECS):c.115-4delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0463 in 1,435,624 control chromosomes in the GnomAD database, including 188 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.040 ( 181 hom., cov: 26)

Exomes 𝑓: 0.047 ( 7 hom. )

Consequence

SEPSECS
NM_016955.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:2

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: Benign. The variant received -10 ACMG points.

BP6

Variant 4-25159110-TA-T is Benign according to our data. Variant chr4-25159110-TA-T is described in CliVar as Benign. Clinvar id is 1296157.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-25159110-TA-T is described in CliVar as Benign. Clinvar id is 1296157.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-25159110-TA-T is described in CliVar as Benign. Clinvar id is 1296157.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-25159110-TA-T is described in CliVar as Benign. Clinvar id is 1296157.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-25159110-TA-T is described in CliVar as Benign. Clinvar id is 1296157.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-25159110-TA-T is described in CliVar as Benign. Clinvar id is 1296157.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-25159110-TA-T is described in CliVar as Benign. Clinvar id is 1296157.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0943 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes

AF:

0.0403

AC:

5680

AN:

141002

Hom.:

181

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0968

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.0155

Gnomad ASJ

AF:

0.0773

Gnomad EAS

AF:

0.00609

Gnomad SAS

AF:

0.0303

Gnomad FIN

AF:

0.0194

Gnomad MID

AF:

0.0357

Gnomad NFE

AF:

0.0159

Gnomad OTH

AF:

0.0354

GnomAD2 exomes

AF:

0.0670

AC:

8604

AN:

128440

AF XY:

0.0676

show subpopulations

Gnomad AFR exome

AF:

0.119

Gnomad AMR exome

AF:

0.0678

Gnomad ASJ exome

AF:

0.112

Gnomad EAS exome

AF:

0.0351

Gnomad FIN exome

AF:

0.0514

Gnomad NFE exome

AF:

0.0631

Gnomad OTH exome

AF:

0.0637

GnomAD4 exome

AF:

0.0469

AC:

60715

AN:

1294540

Hom.:

Cov.:

AF XY:

0.0466

AC XY:

30012

AN XY:

643802

show subpopulations

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

African (AFR)

AF:

0.100

AC:

2756

AN:

27512

American (AMR)

AF:

0.0523

AC:

1521

AN:

29088

Ashkenazi Jewish (ASJ)

AF:

0.0938

AC:

2134

AN:

22752

East Asian (EAS)

AF:

0.0245

AC:

890

AN:

36382

South Asian (SAS)

AF:

0.0558

AC:

3979

AN:

71330

European-Finnish (FIN)

AF:

0.0403

AC:

1888

AN:

46854

Middle Eastern (MID)

AF:

0.0432

AC:

225

AN:

5206

European-Non Finnish (NFE)

AF:

0.0445

AC:

44532

AN:

1001656

Other (OTH)

AF:

0.0519

AC:

2790

AN:

53760

⚠️ 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: 0.309

Heterozygous variant carriers

4107

8214

12322

16429

20536

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1880

3760

5640

7520

9400

<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:

0.0404

AC:

5694

AN:

141084

Hom.:

181

Cov.:

AF XY:

0.0402

AC XY:

2749

AN XY:

68346

show subpopulations

African (AFR)

AF:

0.0969

AC:

3776

AN:

38978

American (AMR)

AF:

0.0155

AC:

218

AN:

14062

Ashkenazi Jewish (ASJ)

AF:

0.0773

AC:

258

AN:

3336

East Asian (EAS)

AF:

0.00610

AC:

AN:

4918

South Asian (SAS)

AF:

0.0304

AC:

134

AN:

4408

European-Finnish (FIN)

AF:

0.0194

AC:

162

AN:

8350

Middle Eastern (MID)

AF:

0.0352

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.0159

AC:

1017

AN:

63936

Other (OTH)

AF:

0.0350

AC:

AN:

1942

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

249

498

748

997

1246

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

186

248

310

<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:

0.00622

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Aug 10, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pontocerebellar hypoplasia type 2D

Benign:1

Sep 27, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-2.4

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over