4-25159110-TAAAAA-TAAAAAAA

Variant names:

• chr4-25159110-T-TAA
• rs34423002
• NM_016955.4:c.115-5_115-4dupTT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BS1

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
• Clinical Significance: Not reported in ClinVar
• 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: G2P, Broad Center for Mendelian Genomics, Ambry Genetics, PanelApp Australia, 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: 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016955.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEPSECS	NM_016955.4	MANE Select	c.115-5_115-4dupTT		splice_region intron	N/A	NP_058651.3	Q9HD40-1
	SEPSECS	NM_001410714.1		c.370-5_370-4dupTT		splice_region intron	N/A	NP_001397643.1	A0A7P0TA23

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEPSECS	ENST00000382103.7	TSL:1 MANE Select	c.115-5_115-4dupTT		splice_region intron	N/A	ENSP00000371535.2	Q9HD40-1
	SEPSECS	ENST00000358971.7	TSL:1	n.252-5_252-4dupTT		splice_region intron	N/A	ENSP00000351857.3	J3KP25
	SEPSECS	ENST00000514585.5	TSL:1	n.114+1144_114+1145dupTT		intron	N/A	ENSP00000421880.1	Q9HD40-2

Frequencies

GnomAD3 genomes AF: 0.000907 AC: 128 AN: 141090 Hom.: 0 Cov.: 26

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

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.: 0 Cov.: 22 AF XY: 0.0293 AC XY: 18605 AN XY: 635790

⚠️ 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), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000956 AC: 135 AN: 141172 Hom.: 0 Cov.: 26 AF XY: 0.000950 AC XY: 65 AN XY: 68406

African (AFR) AF: 0.00169 AC: 66 AN: 38998

American (AMR) AF: 0.000284 AC: 4 AN: 14074

Ashkenazi Jewish (ASJ) AF: 0.000299 AC: 1 AN: 3340

East Asian (EAS) AF: 0.00305 AC: 15 AN: 4918

South Asian (SAS) AF: 0.000227 AC: 1 AN: 4410

European-Finnish (FIN) AF: 0.00120 AC: 10 AN: 8360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.000531 AC: 34 AN: 63976

Other (OTH) AF: 0.00206 AC: 4 AN: 1942

Alfa AF: 0.0000840 Hom.: 12

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.4
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs34423002; hg19: chr4-25160732;