19-19321046-A-C

Position:

• chr19-19321046-A-C

Variant summary

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

The NM_015329.4(MAU2):​c.187A>C​(p.Ile63Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MAU2 NM_015329.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.26

Genes affected

MAU2 (HGNC:29140): (MAU2 sister chromatid cohesion factor) Enables protein N-terminus binding activity. Involved in cohesin loading and maintenance of mitotic sister chromatid cohesion. Located in chromatin and nuclear body. Part of Scc2-Scc4 cohesin loading complex. [provided by Alliance of Genome Resources, Apr 2022]

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=0.2917462).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAU2	NM_015329.4	c.187A>C	p.Ile63Leu	missense_variant	1/19	ENST00000262815.13	NP_056144.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAU2	ENST00000262815.13	c.187A>C	p.Ile63Leu	missense_variant	1/19	1	NM_015329.4	ENSP00000262815.9
MAU2	ENST00000609122.5	c.61A>C	p.Ile21Leu	missense_variant	1/6	4		ENSP00000477034.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460670 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726590

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

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

Sep 25, 2023

The c.187A>C (p.I63L) alteration is located in exon 1 (coding exon 1) of the MAU2 gene. This alteration results from a A to C substitution at nucleotide position 187, causing the isoleucine (I) at amino acid position 63 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	0.21
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.077	T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.075
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.34	N;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.84	N;.
REVEL	Benign	0.20
Sift	Benign	0.28	T;.
Sift4G	Benign	0.26	T;T
Polyphen		0.0020	B;.
Vest4		0.44
MutPred		0.25		Loss of catalytic residue at I63 (P = 0.0738);.;
MVP		0.60
ClinPred		0.74	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.33

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: rs770904152; hg19: chr19-19431855;