4-2238678-C-T

Position:

• chr4-2238678-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001303143.2(HAUS3):​c.1275G>A​(p.Met425Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: HAUS3 NM_001303143.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.768

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.041350037).
• BP6: Variant 4-2238678-C-T is Benign according to our data. Variant chr4-2238678-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3283524.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HAUS3	NM_001303143.2	c.1275G>A	p.Met425Ile	missense_variant	4/6	ENST00000443786.3	NP_001290072.1
POLN	NM_181808.4	c.-13+2842G>A		intron_variant		ENST00000511885.6	NP_861524.2
HAUS3	NM_024511.7	c.1275G>A	p.Met425Ile	missense_variant	3/5		NP_078787.2
COX6B1P5		n.2238678C>T		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HAUS3	ENST00000443786.3	c.1275G>A	p.Met425Ile	missense_variant	4/6	1	NM_001303143.2	ENSP00000392903.2
POLN	ENST00000511885.6	c.-13+2842G>A		intron_variant		5	NM_181808.4	ENSP00000435506.1
ENSG00000290263	ENST00000672725.1	n.1275G>A		non_coding_transcript_exon_variant	3/19			ENSP00000500518.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251036 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135708

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

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: 0.00000411 AC: 6 AN: 1461082 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726888

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

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

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 31, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	14
DANN	Benign	0.75
DEOGEN2	Benign	0.075	.;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.55	T;.;T
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.041	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L;L
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.77	N;N;N
REVEL	Benign	0.064
Sift	Benign	0.97	T;T;T
Sift4G	Benign	0.42	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.20
MutPred		0.25		Loss of disorder (P = 0.0434);Loss of disorder (P = 0.0434);Loss of disorder (P = 0.0434);
MVP		0.076
MPC		0.019
ClinPred		0.0043	T
GERP RS		0.74
Varity_R		0.075
gMVP		0.080

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1467068977; hg19: chr4-2240405;