4-2236392-C-G

Position:

• chr4-2236392-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001303143.2(HAUS3):​c.1414G>C​(p.Glu472Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HAUS3 NM_001303143.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.63

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]

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]

ENSG00000290263 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29399908).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HAUS3	NM_001303143.2	c.1414G>C	p.Glu472Gln	missense_variant	5/6	ENST00000443786.3	NP_001290072.1
POLN	NM_181808.4	c.-13+5128G>C		intron_variant		ENST00000511885.6	NP_861524.2
HAUS3	NM_024511.7	c.1414G>C	p.Glu472Gln	missense_variant	4/5		NP_078787.2
COX6B1P5		n.2236392C>G		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HAUS3	ENST00000443786.3	c.1414G>C	p.Glu472Gln	missense_variant	5/6	1	NM_001303143.2	ENSP00000392903.2
POLN	ENST00000511885.6	c.-13+5128G>C		intron_variant		5	NM_181808.4	ENSP00000435506.1
ENSG00000290263	ENST00000672725.1	n.1414G>C		non_coding_transcript_exon_variant	4/19			ENSP00000500518.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2024

The c.1414G>C (p.E472Q) alteration is located in exon 4 (coding exon 3) of the HAUS3 gene. This alteration results from a G to C substitution at nucleotide position 1414, causing the glutamic acid (E) at amino acid position 472 to be replaced by a glutamine (Q). 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	0.12
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	.;T;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.72	T;.;T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.7	M;M;M
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.91	N;N;N
REVEL	Benign	0.15
Sift	Uncertain	0.015	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.84	.;P;P
Vest4		0.37
MutPred		0.46		Gain of ubiquitination at K477 (P = 0.1204);Gain of ubiquitination at K477 (P = 0.1204);Gain of ubiquitination at K477 (P = 0.1204);
MVP		0.39
MPC		0.050
ClinPred		0.89	D
GERP RS		4.9
Varity_R		0.14
gMVP		0.20

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-2238119; COSMIC: COSV54723922; COSMIC: COSV54723922;