17-28364287-A-T

Variant names:

• chr17-28364287-A-T
• rs782522260
• NM_001080837.4:c.554T>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001080837.4(SEBOX):​c.554T>A​(p.Val185Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,455,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SEBOX NM_001080837.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.180

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]

ENSG00000258924 (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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1391742).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEBOX	NM_001080837.4	c.554T>A	p.Val185Asp	missense_variant	Exon 3 of 3	ENST00000536498.6	NP_001074306.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEBOX	ENST00000536498.6	c.554T>A	p.Val185Asp	missense_variant	Exon 3 of 3	5	NM_001080837.4	ENSP00000444503.3
ENSG00000258924	ENST00000591482.1	n.555+3440A>T		intron_variant	Intron 5 of 5	2
ENSG00000273171	ENST00000555059.2	c.*405T>A		downstream_gene_variant		4		ENSP00000452347.3
SARM1	ENST00000379061.8	n.-69A>T		upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000842 AC: 2 AN: 237534 Hom.: 0 AF XY: 0.0000156 AC XY: 2 AN XY: 128544

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000186

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1455568 Hom.: 0 Cov.: 29 AF XY: 0.00000415 AC XY: 3 AN XY: 723286

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.632T>A (p.V211D) alteration is located in exon 3 (coding exon 3) of the SEBOX gene. This alteration results from a T to A substitution at nucleotide position 632, causing the valine (V) at amino acid position 211 to be replaced by an aspartic acid (D). 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	0.16
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	15
DANN	Benign	0.81
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.55
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.14	T
MetaSVM	Uncertain	-0.099	T
PrimateAI	Benign	0.36	T
REVEL	Benign	0.28
Sift4G	Uncertain	0.0040	D
Vest4		0.28
MVP		0.14
ClinPred		0.048	T
GERP RS		4.2
gMVP		0.80

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

LitVar

Other links and lift over

dbSNP: rs782522260; hg19: chr17-26691309;