Genetic Variant ASB18:p.Arg439Met (chr2-236194957-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_212556.4(ASB18):c.1316G>T(p.Arg439Met) 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 1,461,536 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. R439T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ASB18
NM_212556.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.290

Publications

0 publications found

Variant links:

Genes affected

ASB18 (HGNC:19770): (ankyrin repeat and SOCS box containing 18) 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 a 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. [provided by RefSeq, Feb 2017]

ASB18 links:

GBX2-AS1 (HGNC:55714): (GBX2 and ASB18 antisense RNA 1)

GBX2-AS1 links:

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ACMG classification

Classification was made for transcript

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=0.20820922).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_212556.4. 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
	ASB18	NM_212556.4	MANE Select	c.1316G>T	p.Arg439Met	missense	Exon 6 of 6	NP_997721.2	Q6ZVZ8-1
	GBX2-AS1	NR_186035.1		n.229-18706C>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ASB18	ENST00000409749.8	TSL:1 MANE Select	c.1316G>T	p.Arg439Met	missense	Exon 6 of 6	ENSP00000386532.3	Q6ZVZ8-1
ASB18	ENST00000645891.1		c.1229G>T	p.Arg410Met	missense	Exon 5 of 5	ENSP00000496134.1	Q6ZVZ8-2
GBX2-AS1	ENST00000415226.1	TSL:4	n.223+27288C>A		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461536

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727024

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86184

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111814

Other (OTH)

AF:

0.00

AC:

AN:

60366

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.16

Eigen

Benign

-0.81

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.14

M_CAP

Benign

0.021

MetaRNN

Benign

0.21

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.6

PhyloP100

0.29

PrimateAI

Benign

0.26

PROVEAN

Uncertain

-3.4

REVEL

Benign

0.10

Sift

Uncertain

0.010

Sift4G

Uncertain

0.018

Polyphen

0.78

Vest4

0.30

MutPred

0.62

Loss of MoRF binding (P = 0.0809)

MVP

0.22

MPC

0.35

ClinPred

0.61

GERP RS

-0.90

Varity_R

0.11

gMVP

0.30

Mutation Taster

=96/4

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over