NM_001270.4:c.5102C>T

Variant names:

• chr5-98856411-G-A
• rs755428560
• NM_001270.4:c.5102C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_001270.4(CHD1):​c.5102C>T​(p.Pro1701Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000226 in 1,461,178 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: CHD1 NM_001270.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.11
• Publications: 0 publications found

Genes affected

CHD1 (HGNC:1915): (chromodomain helicase DNA binding protein 1) The CHD family of proteins is characterized by the presence of chromo (chromatin organization modifier) domains and SNF2-related helicase/ATPase domains. CHD genes alter gene expression possibly by modification of chromatin structure thus altering access of the transcriptional apparatus to its chromosomal DNA template. [provided by RefSeq, Jul 2008]

CHD1 Gene-Disease associations (from GenCC):

• Pilarowski-Bjornsson syndrome

  Inheritance: AD, Unknown Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• complex neurodevelopmental disorder

  Inheritance: AR, AD Classification: LIMITED Submitted by: Ambry Genetics, ClinGen

ENSG00000295348 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000226 (33/1461178) while in subpopulation SAS AF = 0.000209 (18/86240). AF 95% confidence interval is 0.000134. There are 0 homozygotes in GnomAdExome4. There are 21 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001270.4. 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
	CHD1	NM_001270.4	MANE Select	c.5102C>T	p.Pro1701Leu	missense	Exon 36 of 36	NP_001261.2	O14646-1
	CHD1	NM_001364113.3		c.5366C>T	p.Pro1789Leu	missense	Exon 37 of 37	NP_001351042.1	A0A087WVF4
	CHD1	NM_001376194.2		c.5102C>T	p.Pro1701Leu	missense	Exon 36 of 36	NP_001363123.1	O14646-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD1	ENST00000614616.5	TSL:5 MANE Select	c.5102C>T	p.Pro1701Leu	missense	Exon 36 of 36	ENSP00000483667.1	O14646-1
	CHD1	ENST00000511067.3	TSL:5	c.5366C>T	p.Pro1789Leu	missense	Exon 37 of 37	ENSP00000479403.2	A0A087WVF4
	CHD1	ENST00000926040.1		c.5102C>T	p.Pro1701Leu	missense	Exon 36 of 36	ENSP00000596099.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000319 AC: 8 AN: 251152 AF XY: 0.0000516

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1461178 Hom.: 0 Cov.: 30 AF XY: 0.0000289 AC XY: 21 AN XY: 726836

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.0000224 AC: 1 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111434

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000412 AC: 5

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.092	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		9.1
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.59
MutPred		0.15		Loss of glycosylation at P1701 (P = 0.0589)
MVP		0.84
MPC		0.045
ClinPred		0.54	D
GERP RS		5.8
Varity_R		0.15
gMVP		0.47
Mutation Taster		=40/60	disease causing

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: rs755428560; hg19: chr5-98192115;