7-123616378-C-T

Variant names:

• chr7-123616378-C-T
• rs1344917905
• NM_001290258.2:c.175C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001290258.2(ASB15):​c.175C>T​(p.Leu59Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,457,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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: ASB15 NM_001290258.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.90

Genes affected

ASB15 (HGNC:19767): (ankyrin repeat and SOCS box containing 15) This gene encodes a member of the suppressor of cytokine signaling box superfamily. The proteins in this superfamily participate in the ubiquitin-proteasome system for the degradation of proteins in the cell cycle and signal transduction pathways. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

ASB15-AS1 (HGNC:40904): (ASB15 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.745

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASB15	NM_001290258.2	c.175C>T	p.Leu59Phe	missense_variant	Exon 6 of 12	ENST00000451215.6	NP_001277187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASB15	ENST00000451215.6	c.175C>T	p.Leu59Phe	missense_variant	Exon 6 of 12	2	NM_001290258.2	ENSP00000416433.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250706 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135512

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1457658 Hom.: 0 Cov.: 33 AF XY: 0.00000276 AC XY: 2 AN XY: 725264

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.175C>T (p.L59F) alteration is located in exon 4 (coding exon 3) of the ASB15 gene. This alteration results from a C to T substitution at nucleotide position 175, causing the leucine (L) at amino acid position 59 to be replaced by a phenylalanine (F). 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	Uncertain	0.49
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.040	T;T;.;T;.;T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	.;.;T;.;T;T
M_CAP	Benign	0.046	D
MetaRNN	Pathogenic	0.74	D;D;D;D;D;D
MetaSVM	Uncertain	0.044	D
MutationAssessor	Pathogenic	3.1	M;M;.;M;.;M
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.0	D;D;D;D;D;D
REVEL	Benign	0.28
Sift	Uncertain	0.0020	D;D;D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;D
Vest4		0.65
MutPred		0.57		Loss of catalytic residue at L59 (P = 0.1274);Loss of catalytic residue at L59 (P = 0.1274);Loss of catalytic residue at L59 (P = 0.1274);Loss of catalytic residue at L59 (P = 0.1274);Loss of catalytic residue at L59 (P = 0.1274);Loss of catalytic residue at L59 (P = 0.1274);
MVP		0.70
MPC		0.64
ClinPred		0.97	D
GERP RS		5.9
Varity_R		0.46
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1344917905; hg19: chr7-123256432;