1-6111775-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4 BS1_Supporting BS2

The NM_015557.3(CHD5):c.5249C>T(p.Thr1750Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000665 in 1,613,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00067 (0 hom.)
• Consequence: CHD5 NM_015557.3 missense, splice_region
• Scores: Splicing: ADA: 0.8243
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.27

Genes affected

CHD5 (HGNC:16816): (chromodomain helicase DNA binding protein 5) This gene encodes a member of the chromodomain helicase DNA-binding protein family. Members of this family are characterized by a chromodomain, a helicase ATP-binding domain and an additional functional domain. This gene encodes a neuron-specific protein that may function in chromatin remodeling and gene transcription. This gene is a potential tumor suppressor gene that may play a role in the development of neuroblastoma. [provided by RefSeq, Feb 2012]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CHD5
• BP4: Computational evidence support a benign effect (MetaRNN=0.2935361).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000643 (98/152306) while in subpopulation AMR AF= 0.00118 (18/15292). AF 95% confidence interval is 0.000769. There are 0 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 98 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD5	NM_015557.3	c.5249C>T	p.Thr1750Met	missense_variant, splice_region_variant	36/42	ENST00000262450.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD5	ENST00000262450.8	c.5249C>T	p.Thr1750Met	missense_variant, splice_region_variant	36/42	1	NM_015557.3	P1
CHD5	ENST00000462991.5	c.*321C>T		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	26/31	1
CHD5	ENST00000377999.5	c.*1819C>T		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	16/21	2
CHD5	ENST00000496404.1	c.*289C>T		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	28/34	2

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 98 AN: 152188 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

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: 0.000955

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000608 AC: 152 AN: 249816 Hom.: 0 AF XY: 0.000621 AC XY: 84 AN XY: 135356

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000926

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000667 AC: 975 AN: 1460700 Hom.: 0 Cov.: 31 AF XY: 0.000654 AC XY: 475 AN XY: 726696

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00141

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.000778

Gnomad4 OTH exome AF: 0.000596

GnomAD4 genome AF: 0.000643 AC: 98 AN: 152306 Hom.: 0 Cov.: 31 AF XY: 0.000564 AC XY: 42 AN XY: 74470

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000956

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000840 Hom.: 0

Bravo AF: 0.000620

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000544 AC: 66

EpiCase AF: 0.000872

EpiControl AF: 0.00107

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

This variant was identified as compound heterozygous. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Uncertain	0.13
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	0.57	D
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.38
Sift	Benign	0.078	T
Sift4G	Benign	0.062	T
Polyphen		0.99	D
Vest4		0.73
MVP		0.83
MPC		1.3
ClinPred		0.10	T
GERP RS		4.8
Varity_R		0.15
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.82
dbscSNV1_RF	Benign	0.69
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: rs139581412; hg19: chr1-6171835; COSMIC: COSV104389822;