4-2231980-C-A

Variant names:

• chr4-2231980-C-A
• rs768527117
• NM_001303143.2:c.1759G>T

Variant summary

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

The NM_001303143.2(HAUS3):​c.1759G>T​(p.Val587Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000301 in 1,330,672 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: HAUS3 NM_001303143.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.47

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 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.1759G>T	p.Val587Leu	missense_variant	Exon 6 of 6	ENST00000443786.3	NP_001290072.1
POLN	NM_181808.4	c.-12-2737G>T		intron_variant	Intron 2 of 25	ENST00000511885.6	NP_861524.2
HAUS3	NM_024511.7	c.1759G>T	p.Val587Leu	missense_variant	Exon 5 of 5		NP_078787.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HAUS3	ENST00000443786.3	c.1759G>T	p.Val587Leu	missense_variant	Exon 6 of 6	1	NM_001303143.2	ENSP00000392903.2
POLN	ENST00000511885.6	c.-12-2737G>T		intron_variant	Intron 2 of 25	5	NM_181808.4	ENSP00000435506.1
ENSG00000290263	ENST00000672725.1	n.1579-2737G>T		intron_variant	Intron 4 of 18			ENSP00000500518.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000859 AC: 2 AN: 232934 Hom.: 0 AF XY: 0.0000159 AC XY: 2 AN XY: 126088

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000115

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000301 AC: 4 AN: 1330672 Hom.: 0 Cov.: 22 AF XY: 0.00000300 AC XY: 2 AN XY: 667542

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000778

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.77	.;T
M_CAP	Benign	0.083	D
MetaRNN	Uncertain	0.49	T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.6	M;M
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.9	N;N
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.34
MutPred		0.64		Loss of methylation at K584 (P = 0.0963);Loss of methylation at K584 (P = 0.0963);
MVP		0.74
MPC		0.065
ClinPred		0.93	D
GERP RS		6.0
Varity_R		0.32
gMVP		0.43

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

Other links and lift over

dbSNP: rs768527117; hg19: chr4-2233707;