rs17408685

Variant names:

• chr4-25125687-T-C
• rs17408685
• NM_016955.4:c.1211+7A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000382103.7(SEPSECS):​c.1211+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0357 in 1,595,370 control chromosomes in the GnomAD database, including 1,356 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (203 hom., cov: 32)
  • Exomes 𝑓: 0.035 (1153 hom.)
• Consequence: SEPSECS ENST00000382103.7 splice_region, intron
• Scores: Splicing: ADA: 0.0001280
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.37
• 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: 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 4-25125687-T-C is Benign according to our data. Variant chr4-25125687-T-C is described in ClinVar as Benign. ClinVar VariationId is 130287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000382103.7. 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.1211+7A>G		splice_region intron	N/A	NP_058651.3
	SEPSECS	NM_001410714.1		c.1466+7A>G		splice_region 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.1211+7A>G		splice_region intron	N/A	ENSP00000371535.2
	SEPSECS	ENST00000358971.7	TSL:1	n.*1009+7A>G		splice_region intron	N/A	ENSP00000351857.3
	SEPSECS	ENST00000514585.5	TSL:1	n.*912+7A>G		splice_region intron	N/A	ENSP00000421880.1

Frequencies

GnomAD3 genomes AF: 0.0461 AC: 7006 AN: 152102 Hom.: 205 Cov.: 32

Gnomad AFR AF: 0.0684

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0332

Gnomad ASJ AF: 0.0612

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.0528

Gnomad FIN AF: 0.0210

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0304

Gnomad OTH AF: 0.0517

GnomAD2 exomes AF: 0.0432 AC: 10738 AN: 248298 AF XY: 0.0422

Gnomad AFR exome AF: 0.0695

Gnomad AMR exome AF: 0.0199

Gnomad ASJ exome AF: 0.0662

Gnomad EAS exome AF: 0.149

Gnomad FIN exome AF: 0.0180

Gnomad NFE exome AF: 0.0316

Gnomad OTH exome AF: 0.0406

GnomAD4 exome AF: 0.0346 AC: 49969 AN: 1443150 Hom.: 1153 Cov.: 27 AF XY: 0.0349 AC XY: 25077 AN XY: 718994

African (AFR) AF: 0.0709 AC: 2343 AN: 33054

American (AMR) AF: 0.0214 AC: 954 AN: 44480

Ashkenazi Jewish (ASJ) AF: 0.0643 AC: 1667 AN: 25914

East Asian (EAS) AF: 0.129 AC: 5096 AN: 39544

South Asian (SAS) AF: 0.0465 AC: 3974 AN: 85532

European-Finnish (FIN) AF: 0.0195 AC: 1041 AN: 53256

Middle Eastern (MID) AF: 0.0419 AC: 240 AN: 5722

European-Non Finnish (NFE) AF: 0.0289 AC: 31698 AN: 1095972

Other (OTH) AF: 0.0495 AC: 2956 AN: 59676

GnomAD4 genome AF: 0.0461 AC: 7011 AN: 152220 Hom.: 203 Cov.: 32 AF XY: 0.0457 AC XY: 3405 AN XY: 74430

African (AFR) AF: 0.0683 AC: 2838 AN: 41542

American (AMR) AF: 0.0332 AC: 507 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0612 AC: 212 AN: 3464

East Asian (EAS) AF: 0.147 AC: 757 AN: 5166

South Asian (SAS) AF: 0.0535 AC: 258 AN: 4822

European-Finnish (FIN) AF: 0.0210 AC: 223 AN: 10616

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0304 AC: 2069 AN: 68004

Other (OTH) AF: 0.0511 AC: 108 AN: 2112

Alfa AF: 0.0367 Hom.: 178

Bravo AF: 0.0485

Asia WGS AF: 0.0950 AC: 328 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Pontocerebellar hypoplasia type 2D (3)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.29
DANN	Benign	0.74
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.0
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: rs17408685; hg19: chr4-25127309; COSMIC: COSV57204715; COSMIC: COSV57204715;