4-2238745-C-A

Variant names:

• chr4-2238745-C-A
• NM_001303143.2:c.1208G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001303143.2(HAUS3):​c.1208G>T​(p.Arg403Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HAUS3 NM_001303143.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.75

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:):

COX6B1P5 (HGNC:37675): (cytochrome c oxidase subunit 6B1 pseudogene 5)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAUS3	NM_001303143.2	c.1208G>T	p.Arg403Leu	missense_variant	Exon 4 of 6	ENST00000443786.3	NP_001290072.1
POLN	NM_181808.4	c.-13+2775G>T		intron_variant	Intron 2 of 25	ENST00000511885.6	NP_861524.2
HAUS3	NM_024511.7	c.1208G>T	p.Arg403Leu	missense_variant	Exon 3 of 5		NP_078787.2
COX6B1P5		n.2238745C>A		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HAUS3	ENST00000443786.3	c.1208G>T	p.Arg403Leu	missense_variant	Exon 4 of 6	1	NM_001303143.2	ENSP00000392903.2
POLN	ENST00000511885.6	c.-13+2775G>T		intron_variant	Intron 2 of 25	5	NM_181808.4	ENSP00000435506.1
ENSG00000290263	ENST00000672725.1	n.1208G>T		non_coding_transcript_exon_variant	Exon 3 of 19			ENSP00000500518.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 09, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1208G>T (p.R403L) alteration is located in exon 3 (coding exon 2) of the HAUS3 gene. This alteration results from a G to T substitution at nucleotide position 1208, causing the arginine (R) at amino acid position 403 to be replaced by a leucine (L). 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	0.13
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	.;D;D
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.86	D;.;D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.46	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;M;M
PrimateAI	Benign	0.20	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Benign	0.19
Sift	Benign	0.11	T;T;T
Sift4G	Benign	0.18	T;T;T
Polyphen		0.85	.;P;P
Vest4		0.59
MutPred		0.31		Loss of MoRF binding (P = 0.0305);Loss of MoRF binding (P = 0.0305);Loss of MoRF binding (P = 0.0305);
MVP		0.51
MPC		0.073
ClinPred		0.96	D
GERP RS		2.3
Varity_R		0.099
gMVP		0.27

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: chr4-2240472;