Genetic Variant NM_017858.3:c.50A>G (chr15-66352898-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_017858.3(TIPIN):c.50A>G(p.His17Arg) 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 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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: 6.8e-7 ( 0 hom. )

Consequence

TIPIN
NM_017858.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.631

Publications

0 publications found

Variant links:

Genes affected

TIPIN (HGNC:30750): (TIMELESS interacting protein) The protein encoded by this gene is part of the replisome complex, a group of proteins that support DNA replication. It binds TIM, which is involved in circadian rhythm regulation, and aids in protecting cells against DNA damage and stress. Two pseudogenes and two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]

TIPIN links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06376615).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017858.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TIPIN	NM_017858.3	MANE Select	c.50A>G	p.His17Arg	missense	Exon 2 of 8	NP_060328.3	Q9BVW5
TIPIN	NM_001398281.1		c.50A>G	p.His17Arg	missense	Exon 2 of 8	NP_001385210.1	Q9BVW5
TIPIN	NM_001398282.1		c.50A>G	p.His17Arg	missense	Exon 2 of 8	NP_001385211.1	Q9BVW5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TIPIN	ENST00000261881.9	TSL:1 MANE Select	c.50A>G	p.His17Arg	missense	Exon 2 of 8	ENSP00000261881.4	Q9BVW5
TIPIN	ENST00000851323.1		c.50A>G	p.His17Arg	missense	Exon 2 of 8	ENSP00000521382.1
TIPIN	ENST00000851324.1		c.50A>G	p.His17Arg	missense	Exon 1 of 7	ENSP00000521383.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461836

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727222

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:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111986

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.0072

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.092

LIST_S2

Benign

0.61

M_CAP

Benign

0.0032

MetaRNN

Benign

0.064

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

PhyloP100

0.63

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.5

REVEL

Benign

0.11

Sift

Benign

0.054

Sift4G

Benign

0.13

Polyphen

0.0030

Vest4

0.23

MutPred

0.072

Loss of catalytic residue at E19 (P = 0.1582)

MVP

0.39

MPC

0.12

ClinPred

0.28

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.073

gMVP

0.13

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over