rs538721924

Variant names:

• chr17-28364929-G-A
• rs538721924
• NM_001080837.4:c.58C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-28364929-G-A
• chr17-28364929-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001080837.4(SEBOX):​c.58C>T​(p.Arg20Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,612,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R20Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: SEBOX NM_001080837.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.820
• Publications: 0 publications found

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]

ENSG00000273171 (HGNC:):

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22086897).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEBOX	NM_001080837.4	c.58C>T	p.Arg20Trp	missense_variant	Exon 2 of 3	ENST00000536498.6	NP_001074306.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEBOX	ENST00000536498.6	c.58C>T	p.Arg20Trp	missense_variant	Exon 2 of 3	5	NM_001080837.4	ENSP00000444503.3
ENSG00000273171	ENST00000555059.2	c.356C>T	p.Pro119Leu	missense_variant	Exon 3 of 4	4		ENSP00000452347.3
SARM1	ENST00000379061.8	n.121-187G>A		intron_variant	Intron 1 of 10	2
ENSG00000258924	ENST00000591482.1	n.555+4082G>A		intron_variant	Intron 5 of 5	2

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000244 AC: 6 AN: 246032 AF XY: 0.0000225

Gnomad AFR exome AF: 0.0000659

Gnomad AMR exome AF: 0.0000585

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000269

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1460314 Hom.: 0 Cov.: 33 AF XY: 0.0000207 AC XY: 15 AN XY: 726310

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.0000449 AC: 2 AN: 44498

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85984

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53286

Middle Eastern (MID) AF: 0.000178 AC: 1 AN: 5632

European-Non Finnish (NFE) AF: 0.0000234 AC: 26 AN: 1111432

Other (OTH) AF: 0.00 AC: 0 AN: 60292

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5 AN XY: 74476

African (AFR) AF: 0.000192 AC: 8 AN: 41566

American (AMR) AF: 0.0000654 AC: 1 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.136C>T (p.R46W) alteration is located in exon 2 (coding exon 2) of the SEBOX gene. This alteration results from a C to T substitution at nucleotide position 136, causing the arginine (R) at amino acid position 46 to be replaced by a tryptophan (W). 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	0.093
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	0.070
CADD	Benign	19
DANN	Uncertain	1.0
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.22	T
PhyloP100		0.82
Sift4G	Pathogenic	0.0	D
MVP		0.64
ClinPred		0.64	D
GERP RS		2.2
PromoterAI		0.014	Neutral
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs538721924; hg19: chr17-26691951; COSMIC: COSV52648307; COSMIC: COSV52648307;