NM_016955.4:c.115-6_115-4dupTTT

Variant names:

• chr4-25159110-T-TAAA
• rs34423002
• NM_016955.4:c.115-6_115-4dupTTT

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
• 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: 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.115-6_115-4dupTTT		splice_region intron	N/A	NP_058651.3	Q9HD40-1
	SEPSECS	NM_001410714.1		c.370-6_370-4dupTTT		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.115-6_115-4dupTTT		splice_region intron	N/A	ENSP00000371535.2	Q9HD40-1
	SEPSECS	ENST00000358971.7	TSL:1	n.252-6_252-4dupTTT		splice_region intron	N/A	ENSP00000351857.3	J3KP25
	SEPSECS	ENST00000514585.5	TSL:1	n.114+1143_114+1145dupTTT		intron	N/A	ENSP00000421880.1	Q9HD40-2

Frequencies

GnomAD3 genomes AF: 0.00000708 AC: 1 AN: 141156 Hom.: 0 Cov.: 26

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

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.: 0 Cov.: 22 AF XY: 0.00149 AC XY: 972 AN XY: 654292

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

African (AFR) AF: 0.00329 AC: 91 AN: 27694

American (AMR) AF: 0.00132 AC: 39 AN: 29442

Ashkenazi Jewish (ASJ) AF: 0.00152 AC: 35 AN: 23084

East Asian (EAS) AF: 0.00154 AC: 57 AN: 36928

South Asian (SAS) AF: 0.00209 AC: 150 AN: 71916

European-Finnish (FIN) AF: 0.000416 AC: 20 AN: 48048

Middle Eastern (MID) AF: 0.000572 AC: 3 AN: 5244

European-Non Finnish (NFE) AF: 0.00152 AC: 1551 AN: 1018950

Other (OTH) AF: 0.00149 AC: 81 AN: 54526

⚠️ 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: 0.00000708 AC: 1 AN: 141156 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 68344

African (AFR) AF: 0.00 AC: 0 AN: 38896

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: 0.000119 AC: 1 AN: 8390

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64008

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

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;