16-30445402-C-T

Variant names:

• chr16-30445402-C-T
• rs199977814
• NM_012248.4:c.326G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_012248.4(SEPHS2):​c.326G>A​(p.Ser109Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000521 in 1,598,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (0 hom.)
• Consequence: SEPHS2 NM_012248.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.594

Genes affected

SEPHS2 (HGNC:19686): (selenophosphate synthetase 2) This gene encodes an enzyme that catalyzes the production of monoselenophosphate (MSP) from selenide and ATP. MSP is the selenium donor required for synthesis of selenocysteine (Sec), which is co-translationally incorporated into selenoproteins at in-frame UGA codons that normally signal translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, the Sec insertion sequence (SECIS) element, which is necessary for the recognition of UGA as a Sec codon rather than as a stop signal. This protein is itself a selenoprotein containing a Sec residue at its active site, suggesting the existence of an autoregulatory mechanism. It is preferentially expressed in tissues implicated in the synthesis of selenoproteins and in sites of blood cell development. A pseudogene for this locus has been identified on chromosome 5. [provided by RefSeq, May 2017]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.01179269).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEPHS2	NM_012248.4	c.326G>A	p.Ser109Asn	missense_variant	Exon 1 of 1	ENST00000478753.5	NP_036380.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEPHS2	ENST00000478753.5	c.326G>A	p.Ser109Asn	missense_variant	Exon 1 of 1	6	NM_012248.4	ENSP00000418669.3

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000327 AC: 71 AN: 216946 Hom.: 0 AF XY: 0.000377 AC XY: 45 AN XY: 119500

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000252

Gnomad ASJ exome AF: 0.000441

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000105

Gnomad FIN exome AF: 0.0000624

Gnomad NFE exome AF: 0.000536

Gnomad OTH exome AF: 0.000550

GnomAD4 exome AF: 0.000540 AC: 781 AN: 1445756 Hom.: 0 Cov.: 31 AF XY: 0.000527 AC XY: 379 AN XY: 718674

Gnomad4 AFR exome AF: 0.0000602

Gnomad4 AMR exome AF: 0.000234

Gnomad4 ASJ exome AF: 0.000391

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000826

Gnomad4 FIN exome AF: 0.0000208

Gnomad4 NFE exome AF: 0.000649

Gnomad4 OTH exome AF: 0.000418

GnomAD4 genome AF: 0.000341 AC: 52 AN: 152352 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74510

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000536 Hom.: 0

Bravo AF: 0.000453

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00172 AC: 14

ExAC AF: 0.000375 AC: 45

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 04, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.326G>A (p.S109N) alteration is located in exon 1 (coding exon 1) of the SEPHS2 gene. This alteration results from a G to A substitution at nucleotide position 326, causing the serine (S) at amino acid position 109 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	9.7
DANN	Benign	0.88
DEOGEN2	Benign	0.0069	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.027
Sift	Benign	0.31	T
Sift4G	Benign	0.50	T
Polyphen		0.0010	B
MVP		0.22
ClinPred		0.011	T
GERP RS		1.6
Varity_R		0.054

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199977814; hg19: chr16-30456723;