Genetic Variant SEBOX:p.Ser161Cys (chr17-28364359-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001080837.4(SEBOX):c.482C>G(p.Ser161Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000501 in 1,596,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

SEBOX
NM_001080837.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.688

Publications

0 publications found

Variant links:

Genes affected

SEBOX (HGNC:32942): (SEBOX homeobox) Homeodomain proteins, such as SEBOX, play a key role in coordinating gene expression during development (Cinquanta et al., 2000 [PubMed 10922053]).[supplied by OMIM, Mar 2008]

SEBOX links:

ENSG00000273171 (HGNC:):

ENSG00000273171 links:

SARM1 (HGNC:17074): (sterile alpha and TIR motif containing 1) Enables NAD+ nucleotidase, cyclic ADP-ribose generating and identical protein binding activity. Involved in NAD catabolic process; positive regulation of neuron death; and response to axon injury. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

SARM1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09865403).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEBOX	NM_001080837.4 link	c.482C>G	p.Ser161Cys	missense_variant	Exon 3 of 3	ENST00000536498.6	NP_001074306.3	Q9HB31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SEBOX	ENST00000536498.6 link	c.482C>G	p.Ser161Cys	missense_variant	Exon 3 of 3	5	NM_001080837.4	ENSP00000444503.3	Q9HB31
ENSG00000273171	ENST00000555059.2 link	c.*333C>G		3_prime_UTR_variant	Exon 4 of 4	4		ENSP00000452347.3	H0YJW9
SARM1	ENST00000379061.8 link	n.4G>C		non_coding_transcript_exon_variant	Exon 1 of 11	2
ENSG00000258924	ENST00000591482.1 link	n.555+3512G>C		intron_variant	Intron 5 of 5	2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000826

AC:

AN:

217934

AF XY:

0.0000594

show subpopulations

Gnomad AFR exome

AF:

0.0000788

Gnomad AMR exome

AF:

0.0000661

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000103

Gnomad OTH exome

AF:

0.000545

GnomAD4 exome

AF:

0.0000526

AC:

AN:

1444598

Hom.:

Cov.:

AF XY:

0.0000544

AC XY:

AN XY:

717058

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33158

American (AMR)

AF:

0.000121

AC:

AN:

41276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25776

East Asian (EAS)

AF:

0.00

AC:

AN:

38908

South Asian (SAS)

AF:

0.000203

AC:

AN:

83902

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52320

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.0000435

AC:

AN:

1103648

Other (OTH)

AF:

0.000100

AC:

AN:

59856

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41442

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000135

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000497

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 14, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.560C>G (p.S187C) alteration is located in exon 3 (coding exon 3) of the SEBOX gene. This alteration results from a C to G substitution at nucleotide position 560, causing the serine (S) at amino acid position 187 to be replaced by a cysteine (C). 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

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.90

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.44

M_CAP

Benign

0.044

MetaRNN

Benign

0.099

MetaSVM

Uncertain

-0.13

PhyloP100

0.69

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.7

REVEL

Benign

0.24

Sift

Uncertain

0.0080

Sift4G

Benign

0.077

Vest4

0.18

MVP

0.11

ClinPred

0.036

GERP RS

2.6

gMVP

0.30

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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17-28364359-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over