4-25159110-TAAAAA-TAAA

Variant names:

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

Variant summary

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

The NM_016955.4(SEPSECS):​c.115-5_115-4delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000706 in 1,456,956 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: 𝑓 0.000057 (0 hom., cov: 26)
  • Exomes 𝑓: 0.00078 (0 hom.)
• Consequence: SEPSECS NM_016955.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.13
• 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: Uncertain_significance. The variant received 0 ACMG points.

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_115-4delTT		splice_region intron	N/A	NP_058651.3	Q9HD40-1
	SEPSECS	NM_001410714.1		c.370-5_370-4delTT		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_115-4delTT		splice_region intron	N/A	ENSP00000371535.2	Q9HD40-1
	SEPSECS	ENST00000358971.7	TSL:1	n.252-5_252-4delTT		splice_region intron	N/A	ENSP00000351857.3	J3KP25
	SEPSECS	ENST00000514585.5	TSL:1	n.114+1144_114+1145delTT		intron	N/A	ENSP00000421880.1	Q9HD40-2

Frequencies

GnomAD3 genomes AF: 0.0000567 AC: 8 AN: 141122 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.000103

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: 0.000358

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000156

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00104 AC: 133 AN: 128440 AF XY: 0.00108

Gnomad AFR exome AF: 0.00159

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.00106

Gnomad EAS exome AF: 0.000669

Gnomad FIN exome AF: 0.00105

Gnomad NFE exome AF: 0.00103

Gnomad OTH exome AF: 0.000640

GnomAD4 exome AF: 0.000775 AC: 1020 AN: 1315834 Hom.: 0 AF XY: 0.000784 AC XY: 513 AN XY: 654306

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

African (AFR) AF: 0.00115 AC: 32 AN: 27808

American (AMR) AF: 0.00122 AC: 36 AN: 29410

Ashkenazi Jewish (ASJ) AF: 0.000736 AC: 17 AN: 23104

East Asian (EAS) AF: 0.000270 AC: 10 AN: 37014

South Asian (SAS) AF: 0.000903 AC: 65 AN: 71998

European-Finnish (FIN) AF: 0.000312 AC: 15 AN: 48016

Middle Eastern (MID) AF: 0.000761 AC: 4 AN: 5254

European-Non Finnish (NFE) AF: 0.000778 AC: 793 AN: 1018648

Other (OTH) AF: 0.000879 AC: 48 AN: 54582

⚠️ 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: 0.0000567 AC: 8 AN: 141122 Hom.: 0 Cov.: 26 AF XY: 0.0000878 AC XY: 6 AN XY: 68324

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

African (AFR) AF: 0.000103 AC: 4 AN: 38892

American (AMR) AF: 0.00 AC: 0 AN: 14066

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3340

East Asian (EAS) AF: 0.00 AC: 0 AN: 4930

South Asian (SAS) AF: 0.00 AC: 0 AN: 4426

European-Finnish (FIN) AF: 0.000358 AC: 3 AN: 8378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.0000156 AC: 1 AN: 63990

Other (OTH) AF: 0.00 AC: 0 AN: 1922

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000104438), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 12

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.1
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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;