rs370930723

Variant names:

• chrX-53192985-C-T
• rs370930723
• NM_004187.5:c.4665G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_004187.5(KDM5C):​c.4665G>A​(p.Pro1555Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000481 in 1,164,861 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000048 (0 hom., 1 hem., cov: 20)
  • Exomes 𝑓: 0.000048 (0 hom. 15 hem.)
• Consequence: KDM5C NM_004187.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.87
• Publications: 0 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• X-linked syndromic intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant X-53192985-C-T is Benign according to our data. Variant chrX-53192985-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1579968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.87 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome4 at 15 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.4665G>A	p.Pro1555Pro	synonymous	Exon 26 of 26	NP_004178.2	P41229-1
	KDM5C	NM_001282622.3		c.4662G>A	p.Pro1554Pro	synonymous	Exon 26 of 26	NP_001269551.1	P41229-5
	KDM5C	NM_001353978.3		c.4656G>A	p.Pro1552Pro	synonymous	Exon 26 of 26	NP_001340907.1	P41229-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM5C	ENST00000375401.8	TSL:1 MANE Select	c.4665G>A	p.Pro1555Pro	synonymous	Exon 26 of 26	ENSP00000364550.4	P41229-1
	KDM5C	ENST00000404049.7	TSL:1	c.4662G>A	p.Pro1554Pro	synonymous	Exon 26 of 26	ENSP00000385394.3	P41229-5
	KDM5C	ENST00000935430.1		c.4767G>A	p.Pro1589Pro	synonymous	Exon 27 of 27	ENSP00000605489.1

Frequencies

GnomAD3 genomes AF: 0.0000477 AC: 5 AN: 104849 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.0000349

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000388

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000390

Gnomad OTH AF: 0.000708

GnomAD2 exomes AF: 0.0000201 AC: 3 AN: 149261 AF XY: 0.0000210

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000433

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000147

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000481 AC: 51 AN: 1060012 Hom.: 0 Cov.: 33 AF XY: 0.0000440 AC XY: 15 AN XY: 340910

African (AFR) AF: 0.0000393 AC: 1 AN: 25476

American (AMR) AF: 0.0000319 AC: 1 AN: 31328

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16594

East Asian (EAS) AF: 0.00 AC: 0 AN: 29740

South Asian (SAS) AF: 0.0000622 AC: 3 AN: 48260

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38845

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3860

European-Non Finnish (NFE) AF: 0.0000536 AC: 44 AN: 821610

Other (OTH) AF: 0.0000451 AC: 2 AN: 44299

GnomAD4 genome AF: 0.0000477 AC: 5 AN: 104849 Hom.: 0 Cov.: 20 AF XY: 0.0000352 AC XY: 1 AN XY: 28425

African (AFR) AF: 0.0000349 AC: 1 AN: 28634

American (AMR) AF: 0.00 AC: 0 AN: 9567

Ashkenazi Jewish (ASJ) AF: 0.000388 AC: 1 AN: 2576

East Asian (EAS) AF: 0.00 AC: 0 AN: 3183

South Asian (SAS) AF: 0.00 AC: 0 AN: 2243

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5102

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 199

European-Non Finnish (NFE) AF: 0.0000390 AC: 2 AN: 51281

Other (OTH) AF: 0.000708 AC: 1 AN: 1412

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	1.0
DANN	Benign	0.51
PhyloP100		-1.9
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs370930723; hg19: chrX-53222167; COSMIC: COSV64766002; COSMIC: COSV64766002;