4-25159110-TAAAAA-TAAAAAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_016955.4(SEPSECS):​c.115-4dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.183 in 140,886 control chromosomes in the GnomAD database, including 2,602 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2602 hom., cov: 26)
  • Exomes 𝑓: 0.38 (141 hom.)
  • Failed GnomAD Quality Control
• Consequence: SEPSECS NM_016955.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 4-25159110-T-TA is Benign according to our data. Variant chr4-25159110-T-TA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 212150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.301 is higher than 0.05.

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.115-4dupT		splice_region intron	N/A	NP_058651.3	Q9HD40-1
	SEPSECS	NM_001410714.1		c.370-4dupT		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.115-4dupT		splice_region intron	N/A	ENSP00000371535.2	Q9HD40-1
	SEPSECS	ENST00000358971.7	TSL:1	n.252-4dupT		splice_region intron	N/A	ENSP00000351857.3	J3KP25
	SEPSECS	ENST00000514585.5	TSL:1	n.114+1145dupT		intron	N/A	ENSP00000421880.1	Q9HD40-2

Frequencies

GnomAD3 genomes AF: 0.183 AC: 25816 AN: 140810 Hom.: 2603 Cov.: 26

Gnomad AFR AF: 0.305

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.166

Gnomad SAS AF: 0.149

Gnomad FIN AF: 0.0973

Gnomad MID AF: 0.192

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.194

GnomAD2 exomes AF: 0.367 AC: 47140 AN: 128440 AF XY: 0.370

Gnomad AFR exome AF: 0.348

Gnomad AMR exome AF: 0.383

Gnomad ASJ exome AF: 0.368

Gnomad EAS exome AF: 0.384

Gnomad FIN exome AF: 0.355

Gnomad NFE exome AF: 0.357

Gnomad OTH exome AF: 0.375

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.382 AC: 461716 AN: 1209870 Hom.: 141 Cov.: 22 AF XY: 0.382 AC XY: 229495 AN XY: 601002

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

African (AFR) AF: 0.367 AC: 9729 AN: 26512

American (AMR) AF: 0.354 AC: 9700 AN: 27380

Ashkenazi Jewish (ASJ) AF: 0.362 AC: 7741 AN: 21396

East Asian (EAS) AF: 0.405 AC: 13269 AN: 32732

South Asian (SAS) AF: 0.374 AC: 25035 AN: 66890

European-Finnish (FIN) AF: 0.375 AC: 15832 AN: 42234

Middle Eastern (MID) AF: 0.314 AC: 1533 AN: 4886

European-Non Finnish (NFE) AF: 0.384 AC: 359725 AN: 937764

Other (OTH) AF: 0.382 AC: 19152 AN: 50076

⚠️ 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: 0.183 AC: 25845 AN: 140886 Hom.: 2602 Cov.: 26 AF XY: 0.183 AC XY: 12457 AN XY: 68224

African (AFR) AF: 0.305 AC: 11882 AN: 38940

American (AMR) AF: 0.154 AC: 2165 AN: 14034

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 577 AN: 3340

East Asian (EAS) AF: 0.167 AC: 820 AN: 4912

South Asian (SAS) AF: 0.150 AC: 661 AN: 4402

European-Finnish (FIN) AF: 0.0973 AC: 808 AN: 8300

Middle Eastern (MID) AF: 0.194 AC: 55 AN: 284

European-Non Finnish (NFE) AF: 0.132 AC: 8441 AN: 63862

Other (OTH) AF: 0.193 AC: 376 AN: 1944

Alfa AF: 0.0266 Hom.: 12

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	not provided (1)
-	-	1	Pontocerebellar hypoplasia type 2D (1)

Computational scores

Source: dbNSFP v4.9

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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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;