dbSNP rs782201442: KDM5C:c.*130C>G (chrX-53192837-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001146702.2(KDM5C):c.4047C>G(p.Ile1349Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. I1349I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 19)

Consequence

KDM5C
NM_001146702.2 missense, splice_region

Scores

Splicing: ADA: 0.00006421

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.601

Publications

1 publications found

Variant links:

Genes affected

KDM5C (HGNC:11114): (lysine demethylase 5C) This gene is a member of the SMCY homolog family and encodes a protein with one ARID domain, one JmjC domain, one JmjN domain and two PHD-type zinc fingers. The DNA-binding motifs suggest this protein is involved in the regulation of transcription and chromatin remodeling. Mutations in this gene have been associated with X-linked cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2009]

KDM5C Gene-Disease associations (from GenCC):

syndromic X-linked intellectual disability Claes-Jensen type
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
X-linked syndromic intellectual disability
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen

KDM5C links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001146702.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KDM5C	NM_004187.5	MANE Select	c.*130C>G		3_prime_UTR	Exon 26 of 26	NP_004178.2	P41229-1
KDM5C	NM_001146702.2		c.4047C>G	p.Ile1349Met	missense splice_region	Exon 24 of 24	NP_001140174.1	A0A6M4C8G8
KDM5C	NM_001282622.3		c.*130C>G		3_prime_UTR	Exon 26 of 26	NP_001269551.1	P41229-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KDM5C	ENST00000375401.8	TSL:1 MANE Select	c.*130C>G		3_prime_UTR	Exon 26 of 26	ENSP00000364550.4	P41229-1
KDM5C	ENST00000404049.7	TSL:1	c.*130C>G		3_prime_UTR	Exon 26 of 26	ENSP00000385394.3	P41229-5
KDM5C	ENST00000452825.7	TSL:5	c.4047C>G	p.Ile1349Met	missense splice_region	Exon 24 of 24	ENSP00000445176.1	P41229-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Uncertain

0.039

BayesDel_noAF

Benign

-0.18

CADD

Benign

3.9

(source)

DANN

Uncertain

0.98

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.25

MetaRNN

Uncertain

0.43

MetaSVM

Benign

-0.31

PhyloP100

0.60

PROVEAN

Benign

-1.5

REVEL

Uncertain

0.38

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.011

Vest4

0.44

MVP

0.69

ClinPred

0.12

GERP RS

2.9

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000064

dbscSNV1_RF

Benign

0.062

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over