4-2238650-T-C

Position:

chr4-2238650-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001303143.2(HAUS3):c.1303A>G(p.Ile435Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000949 in 1,611,572 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00037 ( 2 hom., cov: 33)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

HAUS3
NM_001303143.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.361

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 -4 ACMG points.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HAUS3	NM_001303143.2 linkuse as main transcript	c.1303A>G	p.Ile435Val	missense_variant	4/6	ENST00000443786.3	NP_001290072.1	Q68CZ6-1
POLN	NM_181808.4 linkuse as main transcript	c.-13+2870A>G		intron_variant		ENST00000511885.6	NP_861524.2	Q7Z5Q5-1
HAUS3	NM_024511.7 linkuse as main transcript	c.1303A>G	p.Ile435Val	missense_variant	3/5		NP_078787.2	Q68CZ6-1
COX6B1P5	use as main transcript	n.2238650T>C		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HAUS3	ENST00000443786.3 linkuse as main transcript	c.1303A>G	p.Ile435Val	missense_variant	4/6	1	NM_001303143.2	ENSP00000392903.2	Q68CZ6-1
POLN	ENST00000511885.6 linkuse as main transcript	c.-13+2870A>G		intron_variant		5	NM_181808.4	ENSP00000435506.1	Q7Z5Q5-1
ENSG00000290263	ENST00000672725.1 linkuse as main transcript	n.1303A>G		non_coding_transcript_exon_variant	3/19			ENSP00000500518.1	A0A5F9ZHQ7

Frequencies

GnomAD3 genomes

AF:

0.000342

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000124

AC:

AN:

250650

Hom.:

AF XY:

0.000111

AC XY:

AN XY:

135512

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000658

AC:

AN:

1459202

Hom.:

Cov.:

AF XY:

0.0000620

AC XY:

AN XY:

725970

show subpopulations

Gnomad4 AFR exome

AF:

0.00150

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.000564

GnomAD4 genome

AF:

0.000374

AC:

AN:

152370

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74522

show subpopulations

Gnomad4 AFR

AF:

0.00125

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000688

Hom.:

Bravo

AF:

0.000461

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000124

AC:

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

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

Apr 12, 2022

The c.1303A>G (p.I435V) alteration is located in exon 3 (coding exon 2) of the HAUS3 gene. This alteration results from a A to G substitution at nucleotide position 1303, causing the isoleucine (I) at amino acid position 435 to be replaced by a valine (V). 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

0.083

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Benign

0.046

.;T;T

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.040

LIST_S2

Benign

0.47

T;.;T

M_CAP

Benign

0.0035

MetaRNN

Benign

0.0072

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

M;M;M

PrimateAI

Benign

0.32

PROVEAN

Benign

0.26

N;N;N

REVEL

Benign

0.051

Sift

Benign

0.36

T;T;T

Sift4G

Benign

0.52

T;T;T

Polyphen

0.0050

.;B;B

Vest4

0.15

MVP

0.19

MPC

0.018

ClinPred

0.0057

GERP RS

1.8

Varity_R

0.022

gMVP

0.071

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.21

Position offset: 1

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