rs61747281

Variant names:

• chr4-25151984-T-C
• rs61747281
• NM_016955.4:c.780A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_016955.4(SEPSECS):​c.780A>G​(p.Ser260Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00154 in 1,591,588 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (1 hom.)
• Consequence: SEPSECS NM_016955.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.0450
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 4-25151984-T-C is Benign according to our data. Variant chr4-25151984-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 130286.
• BP7: Synonymous conserved (PhyloP=0.045 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00116 (176/152264) while in subpopulation NFE AF = 0.00205 (139/67960). AF 95% confidence interval is 0.00177. There are 0 homozygotes in GnomAd4. There are 83 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.780A>G	p.Ser260Ser	synonymous	Exon 6 of 11	NP_058651.3
	SEPSECS	NM_001410714.1		c.1035A>G	p.Ser345Ser	synonymous	Exon 7 of 12	NP_001397643.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEPSECS	ENST00000382103.7	TSL:1 MANE Select	c.780A>G	p.Ser260Ser	synonymous	Exon 6 of 11	ENSP00000371535.2
	SEPSECS	ENST00000358971.7	TSL:1	n.*578A>G		non_coding_transcript_exon	Exon 7 of 12	ENSP00000351857.3
	SEPSECS	ENST00000514585.5	TSL:1	n.*481A>G		non_coding_transcript_exon	Exon 5 of 10	ENSP00000421880.1

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 176 AN: 152146 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00205

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000983 AC: 247 AN: 251254 AF XY: 0.000987

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00165

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00158 AC: 2274 AN: 1439324 Hom.: 1 Cov.: 26 AF XY: 0.00152 AC XY: 1093 AN XY: 717548

African (AFR) AF: 0.000151 AC: 5 AN: 33030

American (AMR) AF: 0.000537 AC: 24 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00139 AC: 36 AN: 25948

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39408

South Asian (SAS) AF: 0.000140 AC: 12 AN: 85700

European-Finnish (FIN) AF: 0.000506 AC: 27 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00193 AC: 2110 AN: 1091760

Other (OTH) AF: 0.000988 AC: 59 AN: 59688

GnomAD4 genome AF: 0.00116 AC: 176 AN: 152264 Hom.: 0 Cov.: 33 AF XY: 0.00111 AC XY: 83 AN XY: 74450

African (AFR) AF: 0.000457 AC: 19 AN: 41576

American (AMR) AF: 0.000327 AC: 5 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00205 AC: 139 AN: 67960

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00144 Hom.: 1

Bravo AF: 0.00112

EpiCase AF: 0.00180

EpiControl AF: 0.00178

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	4.9
DANN	Benign	0.75
PhyloP100		0.045
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs61747281; hg19: chr4-25153606;