chr4-2231982-A-G

Position:

• chr4-2231982-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001303143.2(HAUS3):​c.1757T>C​(p.Ile586Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0498 in 1,487,268 control chromosomes in the GnomAD database, including 2,493 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.081 (736 hom., cov: 32)
  • Exomes 𝑓: 0.046 (1757 hom.)
• Consequence: HAUS3 NM_001303143.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.58

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012872815).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HAUS3	NM_001303143.2	c.1757T>C	p.Ile586Thr	missense_variant	6/6	ENST00000443786.3
POLN	NM_181808.4	c.-12-2739T>C		intron_variant		ENST00000511885.6
HAUS3	NM_024511.7	c.1757T>C	p.Ile586Thr	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HAUS3	ENST00000443786.3	c.1757T>C	p.Ile586Thr	missense_variant	6/6	1	NM_001303143.2	P1
POLN	ENST00000511885.6	c.-12-2739T>C		intron_variant		5	NM_181808.4	P1

Frequencies

GnomAD3 genomes AF: 0.0805 AC: 12249 AN: 152078 Hom.: 733 Cov.: 32

Gnomad AFR AF: 0.157

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.0666

Gnomad ASJ AF: 0.0683

Gnomad EAS AF: 0.0291

Gnomad SAS AF: 0.0415

Gnomad FIN AF: 0.0539

Gnomad MID AF: 0.0796

Gnomad NFE AF: 0.0487

Gnomad OTH AF: 0.0631

GnomAD3 exomes AF: 0.0590 AC: 13806 AN: 234040 Hom.: 514 AF XY: 0.0555 AC XY: 7036 AN XY: 126674

Gnomad AFR exome AF: 0.153

Gnomad AMR exome AF: 0.0776

Gnomad ASJ exome AF: 0.0610

Gnomad EAS exome AF: 0.0325

Gnomad SAS exome AF: 0.0407

Gnomad FIN exome AF: 0.0612

Gnomad NFE exome AF: 0.0483

Gnomad OTH exome AF: 0.0649

GnomAD4 exome AF: 0.0463 AC: 61831 AN: 1335072 Hom.: 1757 Cov.: 22 AF XY: 0.0463 AC XY: 30996 AN XY: 669478

Gnomad4 AFR exome AF: 0.152

Gnomad4 AMR exome AF: 0.0750

Gnomad4 ASJ exome AF: 0.0576

Gnomad4 EAS exome AF: 0.0356

Gnomad4 SAS exome AF: 0.0419

Gnomad4 FIN exome AF: 0.0580

Gnomad4 NFE exome AF: 0.0412

Gnomad4 OTH exome AF: 0.0531

GnomAD4 genome AF: 0.0806 AC: 12270 AN: 152196 Hom.: 736 Cov.: 32 AF XY: 0.0790 AC XY: 5878 AN XY: 74428

Gnomad4 AFR AF: 0.157

Gnomad4 AMR AF: 0.0664

Gnomad4 ASJ AF: 0.0683

Gnomad4 EAS AF: 0.0289

Gnomad4 SAS AF: 0.0421

Gnomad4 FIN AF: 0.0539

Gnomad4 NFE AF: 0.0487

Gnomad4 OTH AF: 0.0624

Alfa AF: 0.0559 Hom.: 677

Bravo AF: 0.0841

TwinsUK AF: 0.0413 AC: 153

ALSPAC AF: 0.0441 AC: 170

ESP6500AA AF: 0.142 AC: 620

ESP6500EA AF: 0.0513 AC: 435

ExAC AF: 0.0595 AC: 7214

Asia WGS AF: 0.0450 AC: 156 AN: 3430

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.069	T;T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.012
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.62	.;T
MetaRNN	Benign	0.0013	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	0.99	P;P;P;P
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.67	N;N
REVEL	Benign	0.055
Sift	Benign	0.037	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		0.017	B;B
Vest4		0.046
MPC		0.020
ClinPred		0.016	T
GERP RS		4.9
Varity_R		0.054
gMVP		0.090

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11937432; hg19: chr4-2233709;