Variant 19-55347043-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_032701.4(KMT5C):c.983C>A(p.Pro328His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000809 in 1,546,242 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00084 ( 1 hom. )

Consequence

KMT5C
NM_032701.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.577

Variant links:

Genes affected

KMT5C (HGNC:28405): (lysine methyltransferase 5C) SUV420H2 and the related enzyme SUV420H1 (MIM 610881) function as histone methyltransferases that specifically trimethylate nucleosomal histone H4 (see MIM 602822) on lysine-20 (K20) (Schotta et al., 2004 [PubMed 15145825]).[supplied by OMIM, Dec 2009]

KMT5C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.015279025).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT5C	NM_032701.4 linkuse as main transcript	c.983C>A	p.Pro328His	missense_variant	9/9	ENST00000255613.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT5C	ENST00000255613.8 linkuse as main transcript	c.983C>A	p.Pro328His	missense_variant	9/9	1	NM_032701.4	P1	Q86Y97-1
KMT5C	ENST00000630497.1 linkuse as main transcript	c.638C>A	p.Pro213His	missense_variant	7/7	1
KMT5C	ENST00000474492.1 linkuse as main transcript	n.553C>A		non_coding_transcript_exon_variant	3/3	2
KMT5C	ENST00000445196.5 linkuse as main transcript	c.*523C>A		3_prime_UTR_variant, NMD_transcript_variant	8/8	5			Q86Y97-2

Frequencies

GnomAD3 genomes

AF:

0.000532

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000809

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.000526

AC:

113

AN:

215012

Hom.:

AF XY:

0.000548

AC XY:

AN XY:

120422

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000624

Gnomad ASJ exome

AF:

0.000216

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000922

Gnomad OTH exome

AF:

0.000367

GnomAD4 exome

AF:

0.000839

AC:

1170

AN:

1393958

Hom.:

Cov.:

AF XY:

0.000819

AC XY:

570

AN XY:

695996

show subpopulations

Gnomad4 AFR exome

AF:

0.000186

Gnomad4 AMR exome

AF:

0.000610

Gnomad4 ASJ exome

AF:

0.000117

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00103

Gnomad4 OTH exome

AF:

0.000567

GnomAD4 genome

AF:

0.000532

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.000470

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.000980

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000809

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.000579

Hom.:

Bravo

AF:

0.000604

ExAC

AF:

0.000434

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2021

The c.983C>A (p.P328H) alteration is located in exon 9 (coding exon 8) of the KMT5C gene. This alteration results from a C to A substitution at nucleotide position 983, causing the proline (P) at amino acid position 328 to be replaced by a histidine (H). 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

0.096

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.61

CADD

Benign

4.5

DANN

Uncertain

0.98

DEOGEN2

Benign

0.18

T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.064

LIST_S2

Benign

0.49

T;T

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.015

T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-1.9

N;.

REVEL

Benign

0.012

Sift

Benign

0.062

T;.

Sift4G

Uncertain

0.012

D;D

Polyphen

0.0010

B;.

Vest4

0.090

MVP

0.043

MPC

0.58

ClinPred

0.026

GERP RS

0.10

Varity_R

0.073

gMVP

0.13

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over