Genetic Variant HAUS4:p.Arg305His (chr14-22946703-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001166269.2(HAUS4):c.914G>A(p.Arg305His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000755 in 1,457,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

HAUS4
NM_001166269.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.474

Variant links:

Genes affected

HAUS4 (HGNC:20163): (HAUS augmin like complex subunit 4) This gene encodes a subunit of the centrosome complex termed the human augmin complex. The encoded protein localizes to the spindle microtubules and may play a role in mitotic spindle assembly and maintenance of centrosome integrity during cell division. Alternate splicing results in multiple transcript variants. A pseudogene of this gene is found on chromosome 1. [provided by RefSeq, Oct 2009]

HAUS4 links:

ENSG00000259132 (HGNC:):

ENSG00000259132 links:

PRMT5-DT (HGNC:55482): (PRMT5 divergent transcript)

PRMT5-DT links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.101159245).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAUS4	NM_001166269.2 link	c.914G>A	p.Arg305His	missense_variant	Exon 10 of 10	ENST00000541587.6	NP_001159741.1	Q9H6D7-1
HAUS4	NM_017815.3 link	c.914G>A	p.Arg305His	missense_variant	Exon 10 of 10		NP_060285.2	Q9H6D7-1
HAUS4	NM_001166270.2 link	c.779G>A	p.Arg260His	missense_variant	Exon 9 of 9		NP_001159742.1	Q9H6D7-4
PRMT5-DT	NR_110002.1 link	n.195-7628C>T		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HAUS4	ENST00000541587.6 link	c.914G>A	p.Arg305His	missense_variant	Exon 10 of 10	1	NM_001166269.2	ENSP00000441026.1		Q9H6D7-1
ENSG00000259132	ENST00000555074.1 link	c.401G>A	p.Arg134His	missense_variant	Exon 5 of 5	2		ENSP00000450856.2		G3V2T6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000121

AC:

AN:

247766

Hom.:

AF XY:

0.00

AC XY:

AN XY:

133934

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:

0.0000268

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000755

AC:

AN:

1457174

Hom.:

Cov.:

AF XY:

0.00000966

AC XY:

AN XY:

724578

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000226

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:

0.00000811

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000566

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000549

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.914G>A (p.R305H) alteration is located in exon 10 (coding exon 9) of the HAUS4 gene. This alteration results from a G to A substitution at nucleotide position 914, causing the arginine (R) at amino acid position 305 to be replaced by a histidine (H). 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

0.072

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.016

.;T;T;.;.;.;.

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.096

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.78

T;.;T;.;T;.;T

M_CAP

Benign

0.0029

MetaRNN

Benign

0.10

T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

.;M;M;.;.;.;.

PrimateAI

Benign

0.40

PROVEAN

Benign

0.67

N;N;N;N;N;N;N

REVEL

Benign

0.033

Sift

Benign

0.078

T;D;D;T;T;T;T

Sift4G

Benign

0.081

T;T;T;T;T;T;T

Polyphen

0.013, 0.41

.;B;B;B;B;B;B

Vest4

0.20

MVP

0.50

MPC

0.27

ClinPred

0.43

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.049

gMVP

0.15

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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