4-25131742-C-T

Variant names:

• chr4-25131742-C-T
• rs3756207
• NM_016955.4:c.1027-4385G>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.1027-4385G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.818 in 152,176 control chromosomes in the GnomAD database, including 50,910 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 0.82 (50910 hom., cov: 32)
• Consequence: SEPSECS NM_016955.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0480
• Publications: 3 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: Ambry Genetics, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Broad Center for Mendelian Genomics
• 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=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.823 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.1027-4385G>A		intron	N/A	NP_058651.3	Q9HD40-1
	SEPSECS	NM_001410714.1		c.1282-4385G>A		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.1027-4385G>A		intron	N/A	ENSP00000371535.2	Q9HD40-1
	SEPSECS	ENST00000358971.7	TSL:1	n.*825-4385G>A		intron	N/A	ENSP00000351857.3	J3KP25
	SEPSECS	ENST00000514585.5	TSL:1	n.*728-4385G>A		intron	N/A	ENSP00000421880.1	Q9HD40-2

Frequencies

GnomAD3 genomes AF: 0.818 AC: 124349 AN: 152058 Hom.: 50888 Cov.: 32

Gnomad AFR AF: 0.822

Gnomad AMI AF: 0.793

Gnomad AMR AF: 0.826

Gnomad ASJ AF: 0.849

Gnomad EAS AF: 0.668

Gnomad SAS AF: 0.845

Gnomad FIN AF: 0.820

Gnomad MID AF: 0.839

Gnomad NFE AF: 0.821

Gnomad OTH AF: 0.830

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

GnomAD4 genome AF: 0.818 AC: 124420 AN: 152176 Hom.: 50910 Cov.: 32 AF XY: 0.817 AC XY: 60810 AN XY: 74388

African (AFR) AF: 0.822 AC: 34105 AN: 41508

American (AMR) AF: 0.825 AC: 12611 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.849 AC: 2948 AN: 3472

East Asian (EAS) AF: 0.669 AC: 3464 AN: 5180

South Asian (SAS) AF: 0.845 AC: 4077 AN: 4824

European-Finnish (FIN) AF: 0.820 AC: 8680 AN: 10582

Middle Eastern (MID) AF: 0.827 AC: 243 AN: 294

European-Non Finnish (NFE) AF: 0.821 AC: 55821 AN: 68008

Other (OTH) AF: 0.828 AC: 1748 AN: 2110

Alfa AF: 0.824 Hom.: 7603

Bravo AF: 0.819

Asia WGS AF: 0.764 AC: 2659 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.1
DANN	Benign	0.63
PhyloP100		0.048
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: rs3756207; hg19: chr4-25133364;