NM_004187.5:c.*132C>G

Variant names:

• chrX-53192835-G-C
• rs781910906
• NM_004187.5:c.*132C>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_004187.5(KDM5C):​c.*132C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000605 in 1,091,199 control chromosomes in the GnomAD database, including 1 homozygotes. There are 12 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., 8 hem., cov: 19)
  • Exomes 𝑓: 0.000029 (1 hom. 4 hem.)
• Consequence: KDM5C NM_004187.5 3_prime_UTR
• Scores: Splicing: ADA: 0.00006871
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.885
• Publications: 2 publications found

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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• X-linked syndromic intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1330562).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000375 (37/98685) while in subpopulation AMR AF = 0.00379 (34/8977). AF 95% confidence interval is 0.00279. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 19. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Hemizygotes in GnomAd4 at 8 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004187.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM5C	NM_004187.5	MANE Select	c.*132C>G		3_prime_UTR	Exon 26 of 26	NP_004178.2
	KDM5C	NM_001146702.2		c.4049C>G	p.Pro1350Arg	missense splice_region	Exon 24 of 24	NP_001140174.1
	KDM5C	NM_001282622.3		c.*132C>G		3_prime_UTR	Exon 26 of 26	NP_001269551.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM5C	ENST00000375401.8	TSL:1 MANE Select	c.*132C>G		3_prime_UTR	Exon 26 of 26	ENSP00000364550.4
	KDM5C	ENST00000404049.7	TSL:1	c.*132C>G		3_prime_UTR	Exon 26 of 26	ENSP00000385394.3
	KDM5C	ENST00000452825.7	TSL:5	c.4049C>G	p.Pro1350Arg	missense splice_region	Exon 24 of 24	ENSP00000445176.1

Frequencies

GnomAD3 genomes AF: 0.000375 AC: 37 AN: 98628 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00379

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00224

GnomAD2 exomes AF: 0.0000493 AC: 5 AN: 101407 AF XY: 0.0000777

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000179

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000722

GnomAD4 exome AF: 0.0000292 AC: 29 AN: 992514 Hom.: 1 Cov.: 21 AF XY: 0.0000134 AC XY: 4 AN XY: 297710

African (AFR) AF: 0.00 AC: 0 AN: 23843

American (AMR) AF: 0.000681 AC: 18 AN: 26421

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17190

East Asian (EAS) AF: 0.00 AC: 0 AN: 26319

South Asian (SAS) AF: 0.00 AC: 0 AN: 46175

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36750

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3060

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 771080

Other (OTH) AF: 0.000264 AC: 11 AN: 41676

GnomAD4 genome AF: 0.000375 AC: 37 AN: 98685 Hom.: 0 Cov.: 19 AF XY: 0.000352 AC XY: 8 AN XY: 22703

African (AFR) AF: 0.00 AC: 0 AN: 27737

American (AMR) AF: 0.00379 AC: 34 AN: 8977

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2461

East Asian (EAS) AF: 0.00 AC: 0 AN: 2886

South Asian (SAS) AF: 0.00 AC: 0 AN: 1884

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4317

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 179

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 48296

Other (OTH) AF: 0.00220 AC: 3 AN: 1361

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000986

ExAC AF: 0.0000297 AC: 3

ClinVar

ClinVar submissions as Germline

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	7.0
DANN	Benign	0.87
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.24	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.82	T
PhyloP100		0.89
PROVEAN	Benign	0.25	N
REVEL	Benign	0.10
Sift	Benign	0.27	T
Sift4G	Benign	0.16	T
Vest4		0.48
MutPred		0.51		Loss of loop (P = 0.0073)
MVP		0.63
ClinPred		0.026	T
GERP RS		0.98
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000069
dbscSNV1_RF	Benign	0.0080
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

Other links and lift over

dbSNP: rs781910906; hg19: chrX-53222017;