chr2-53765548-C-T

Variant names:

• chr2-53765548-C-T
• rs373945186
• NM_016115.5:c.25G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016115.5(ASB3):​c.25G>A​(p.Asp9Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D9Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ASB3 NM_016115.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.62
• Publications: 0 publications found

Genes affected

ASB3 (HGNC:16013): (ankyrin repeat and SOCS box containing 3) The protein encoded by this gene is a member of the ankyrin repeat and SOCS box-containing (ASB) family of proteins. They contain ankyrin repeat sequence and SOCS box domain. The SOCS box serves to couple suppressor of cytokine signalling (SOCS) proteins and their binding partners with the elongin B and C complex, possibly targeting them for degradation. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Jan 2011]

GPR75-ASB3 (HGNC:40043): (GPR75-ASB3 readthrough) This locus represents naturally occurring read-through transcription between the neighboring GPR75 (G protein-coupled receptor 75) and ASB3 (ankyrin repeat and SOCS box containing 3) on chromosome 2. The transcript includes exons from both GPR75 and ASB3 and translation initiates in the 5' non-coding exon of GPR75. The resulting protein has a novel N-terminus but is otherwise identical to that encoded by ASB3.[provided by RefSeq, Feb 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28020737).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016115.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASB3	NM_016115.5	MANE Select	c.25G>A	p.Asp9Asn	missense	Exon 2 of 10	NP_057199.1	Q9Y575-1
	GPR75-ASB3	NM_001164165.2		c.139G>A	p.Asp47Asn	missense	Exon 2 of 10	NP_001157637.1
	ASB3	NM_001201965.2		c.-23-14607G>A		intron	N/A	NP_001188894.1	Q9Y575-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASB3	ENST00000263634.8	TSL:1 MANE Select	c.25G>A	p.Asp9Asn	missense	Exon 2 of 10	ENSP00000263634.2	Q9Y575-1
	ASB3	ENST00000406625.6	TSL:2	c.25G>A	p.Asp9Asn	missense	Exon 2 of 10	ENSP00000385085.4	Q9Y575-1
	ASB3	ENST00000893612.1		c.25G>A	p.Asp9Asn	missense	Exon 2 of 10	ENSP00000563671.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727242

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.045	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.6
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.22
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.026	D
Polyphen		0.93	P
Vest4		0.22
MutPred		0.39		Loss of loop (P = 0.1242)
MVP		0.58
MPC		0.065
ClinPred		0.95	D
GERP RS		3.6
PromoterAI		0.0066	Neutral
Varity_R		0.17
gMVP		0.42
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs373945186; hg19: chr2-53992685;