Genetic Variant HARBI1:p.Met38Thr (chr11-46616125-A-G) – 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_173811.4(HARBI1):c.113T>C(p.Met38Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: 0.0000027 ( 0 hom. )

Consequence

HARBI1
NM_173811.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.08

Publications

0 publications found

Variant links:

Genes affected

HARBI1 (HGNC:26522): (harbinger transposase derived 1) Predicted to enable metal ion binding activity and nuclease activity. Predicted to be involved in nucleic acid phosphodiester bond hydrolysis. Located in centriolar satellite; cytosol; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

HARBI1 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=0.10419345).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HARBI1	NM_173811.4 link	c.113T>C	p.Met38Thr	missense_variant	Exon 2 of 3	ENST00000326737.3	NP_776172.1	Q96MB7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HARBI1	ENST00000326737.3 link	c.113T>C	p.Met38Thr	missense_variant	Exon 2 of 3	1	NM_173811.4	ENSP00000317743.3	Q96MB7
HARBI1	ENST00000529192.1 link	c.113T>C	p.Met38Thr	missense_variant	Exon 2 of 2	3		ENSP00000431697.1	E9PK24
HARBI1	ENST00000532281.1 link	c.113T>C	p.Met38Thr	missense_variant	Exon 2 of 2	3		ENSP00000436232.1	E9PQI1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

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.:

Alfa

AF:

0.0000583

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 30, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.113T>C (p.M38T) alteration is located in exon 2 (coding exon 1) of the HARBI1 gene. This alteration results from a T to C substitution at nucleotide position 113, causing the methionine (M) at amino acid position 38 to be replaced by a threonine (T). 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

0.10

BayesDel_addAF

Benign

-0.083

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.030

T;.;.

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.67

T;T;T

M_CAP

Benign

0.0012

MetaRNN

Benign

0.10

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.6

N;.;.

PhyloP100

1.1

PrimateAI

Uncertain

0.53

PROVEAN

Benign

0.050

N;N;N

REVEL

Benign

0.11

Sift

Benign

0.38

T;T;T

Sift4G

Benign

0.42

T;.;.

Polyphen

0.0

B;.;.

Vest4

0.24

MVP

0.12

MPC

0.19

ClinPred

0.12

GERP RS

4.3

Varity_R

0.063

gMVP

0.45

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over