4-25159110-TAAAAA-TAAAA

Variant names:

• chr4-25159110-TA-T
• rs34423002
• NM_016955.4:c.115-4delT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

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
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -2.42
• Publications: 5 publications found

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

ACMG classification

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 ClinVar 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	c.115-4delT		splice_region_variant, intron_variant	Intron 1 of 10	ENST00000382103.7	NP_058651.3

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0403 AC: 5680 AN: 141002 Hom.: 181 Cov.: 26

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

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.: 7 Cov.: 22 AF XY: 0.0466 AC XY: 30012 AN XY: 643802

⚠️ 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.

GnomAD4 genome AF: 0.0404 AC: 5694 AN: 141084 Hom.: 181 Cov.: 26 AF XY: 0.0402 AC XY: 2749 AN XY: 68346

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: 30 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: 10 AN: 284

European-Non Finnish (NFE) AF: 0.0159 AC: 1017 AN: 63936

Other (OTH) AF: 0.0350 AC: 68 AN: 1942

Alfa AF: 0.00622 Hom.: 12

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

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)

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

Other links and lift over

dbSNP: rs34423002; hg19: chr4-25160732; COSMIC: COSV57205388; COSMIC: COSV57205388;