4-25150252-A-T

Variant names:

• chr4-25150252-A-T
• rs1035091
• NM_016955.4:c.804+1708T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016955.4(SEPSECS):​c.804+1708T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.603 in 152,196 control chromosomes in the GnomAD database, including 28,402 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.60 (28402 hom., cov: 33)
• Consequence: SEPSECS NM_016955.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.955
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.661 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEPSECS	NM_016955.4	MANE Select	c.804+1708T>A		intron	N/A	NP_058651.3
	SEPSECS	NM_001410714.1		c.1059+1708T>A		intron	N/A	NP_001397643.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEPSECS	ENST00000382103.7	TSL:1 MANE Select	c.804+1708T>A		intron	N/A	ENSP00000371535.2
	SEPSECS	ENST00000358971.7	TSL:1	n.*602+1708T>A		intron	N/A	ENSP00000351857.3
	SEPSECS	ENST00000514585.5	TSL:1	n.*505+1708T>A		intron	N/A	ENSP00000421880.1

Frequencies

GnomAD3 genomes AF: 0.604 AC: 91792 AN: 152078 Hom.: 28405 Cov.: 33

Gnomad AFR AF: 0.494

Gnomad AMI AF: 0.677

Gnomad AMR AF: 0.608

Gnomad ASJ AF: 0.584

Gnomad EAS AF: 0.388

Gnomad SAS AF: 0.603

Gnomad FIN AF: 0.729

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.666

Gnomad OTH AF: 0.609

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.603 AC: 91816 AN: 152196 Hom.: 28402 Cov.: 33 AF XY: 0.602 AC XY: 44818 AN XY: 74396

African (AFR) AF: 0.494 AC: 20489 AN: 41504

American (AMR) AF: 0.607 AC: 9280 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.584 AC: 2025 AN: 3468

East Asian (EAS) AF: 0.389 AC: 2019 AN: 5188

South Asian (SAS) AF: 0.602 AC: 2907 AN: 4828

European-Finnish (FIN) AF: 0.729 AC: 7712 AN: 10582

Middle Eastern (MID) AF: 0.595 AC: 175 AN: 294

European-Non Finnish (NFE) AF: 0.666 AC: 45302 AN: 68012

Other (OTH) AF: 0.610 AC: 1290 AN: 2116

Alfa AF: 0.638 Hom.: 3886

Bravo AF: 0.592

Asia WGS AF: 0.501 AC: 1743 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	7.8
DANN	Benign	0.91
PhyloP100		0.95
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: rs1035091; hg19: chr4-25151874;