4-2238703-A-C

Position:

chr4-2238703-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001303143.2(HAUS3):c.1250T>G(p.Met417Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,613,100 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: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

HAUS3
NM_001303143.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.699

Variant links:

Genes affected

HAUS3 (HGNC:28719): (HAUS augmin like complex subunit 3) This gene encodes a component of the HAUS augmin-like protein complex, which plays a key role in cytokinesis and mitosis. Disruption of the encoded protein causes mitotic defects resulting from fragmentation of centrosomes and microtubule destabilization. This gene shares its 5' exons with some transcripts from overlapping GeneID: 353497, which encodes a DNA polymerase. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

HAUS3 links:

POLN (HGNC:18870): (DNA polymerase nu) This gene encodes a DNA polymerase type-A family member. The encoded protein plays a role in DNA repair and homologous recombination. This gene shares its 5' exons with some transcripts from overlapping GeneID: 79441, which encodes an augmentin-like protein complex subunit. [provided by RefSeq, Dec 2014]

POLN links:

ENSG00000290263 (HGNC:):

ENSG00000290263 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04009983).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HAUS3	NM_001303143.2 linkuse as main transcript	c.1250T>G	p.Met417Arg	missense_variant	4/6	ENST00000443786.3	NP_001290072.1	Q68CZ6-1
POLN	NM_181808.4 linkuse as main transcript	c.-13+2817T>G		intron_variant		ENST00000511885.6	NP_861524.2	Q7Z5Q5-1
HAUS3	NM_024511.7 linkuse as main transcript	c.1250T>G	p.Met417Arg	missense_variant	3/5		NP_078787.2	Q68CZ6-1
COX6B1P5	use as main transcript	n.2238703A>C		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HAUS3	ENST00000443786.3 linkuse as main transcript	c.1250T>G	p.Met417Arg	missense_variant	4/6	1	NM_001303143.2	ENSP00000392903.2	Q68CZ6-1
POLN	ENST00000511885.6 linkuse as main transcript	c.-13+2817T>G		intron_variant		5	NM_181808.4	ENSP00000435506.1	Q7Z5Q5-1
ENSG00000290263	ENST00000672725.1 linkuse as main transcript	n.1250T>G		non_coding_transcript_exon_variant	3/19			ENSP00000500518.1	A0A5F9ZHQ7

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251150

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135768

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.0000260

AC:

AN:

1460854

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

726776

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000333

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2021

The c.1250T>G (p.M417R) alteration is located in exon 3 (coding exon 2) of the HAUS3 gene. This alteration results from a T to G substitution at nucleotide position 1250, causing the methionine (M) at amino acid position 417 to be replaced by an arginine (R). 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

0.071

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.54

CADD

Benign

0.10

DANN

Benign

0.63

DEOGEN2

Benign

0.053

.;T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.040

LIST_S2

Benign

0.35

T;.;T

M_CAP

Benign

0.0080

MetaRNN

Benign

0.040

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

M;M;M

PrimateAI

Benign

0.21

PROVEAN

Benign

0.52

N;N;N

REVEL

Benign

0.071

Sift

Benign

0.52

T;T;T

Sift4G

Benign

0.56

T;T;T

Polyphen

0.026

.;B;B

Vest4

0.27

MutPred

0.24

Loss of stability (P = 0.0481);Loss of stability (P = 0.0481);Loss of stability (P = 0.0481);

MVP

0.067

MPC

0.020

ClinPred

0.030

GERP RS

-11

Varity_R

0.13

gMVP

0.15

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over