12-6573102-G-A

Variant names:

• chr12-6573102-G-A
• rs201751048
• NM_001273.5:c.5529C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001273.5(CHD4):​c.5529C>T​(p.Asn1843Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000781 in 1,610,158 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (21 hom.)
• Consequence: CHD4 NM_001273.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.50
• Publications: 1 publications found

Genes affected

CHD4 (HGNC:1919): (chromodomain helicase DNA binding protein 4) The product of this gene belongs to the SNF2/RAD54 helicase family. It represents the main component of the nucleosome remodeling and deacetylase complex and plays an important role in epigenetic transcriptional repression. Patients with dermatomyositis develop antibodies against this protein. Somatic mutations in this gene are associated with serous endometrial tumors. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2014]

CHD4 Gene-Disease associations (from GenCC):

• Sifrim-Hitz-Weiss syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ENSG00000285238 (HGNC:):

CHD4-AS1 (HGNC:58242):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 12-6573102-G-A is Benign according to our data. Variant chr12-6573102-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 764762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.5 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000532 (81/152334) while in subpopulation SAS AF = 0.00807 (39/4830). AF 95% confidence interval is 0.00607. There are 0 homozygotes in GnomAd4. There are 54 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 81 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001273.5. 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
	CHD4	NM_001273.5	MANE Select	c.5529C>T	p.Asn1843Asn	synonymous	Exon 38 of 40	NP_001264.2	Q14839-1
	CHD4	NM_001297553.2		c.5508C>T	p.Asn1836Asn	synonymous	Exon 37 of 39	NP_001284482.1	F5GWX5
	CHD4	NM_001363606.2		c.5496C>T	p.Asn1832Asn	synonymous	Exon 38 of 40	NP_001350535.1	A0A2U3TZM0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD4	ENST00000544040.7	TSL:5 MANE Select	c.5529C>T	p.Asn1843Asn	synonymous	Exon 38 of 40	ENSP00000440542.2	Q14839-1
	CHD4	ENST00000357008.7	TSL:1	c.5496C>T	p.Asn1832Asn	synonymous	Exon 38 of 40	ENSP00000349508.3	A0A2U3TZM0
	ENSG00000285238	ENST00000644480.2		n.*610C>T		non_coding_transcript_exon	Exon 39 of 55	ENSP00000493629.2	A0A2R8Y445

Frequencies

GnomAD3 genomes AF: 0.000532 AC: 81 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00807

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00135 AC: 334 AN: 247070 AF XY: 0.00177

Gnomad AFR exome AF: 0.0000626

Gnomad AMR exome AF: 0.000270

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.0000558

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000365

Gnomad OTH exome AF: 0.000670

GnomAD4 exome AF: 0.000807 AC: 1176 AN: 1457824 Hom.: 21 Cov.: 30 AF XY: 0.00114 AC XY: 823 AN XY: 725030

African (AFR) AF: 0.0000602 AC: 2 AN: 33242

American (AMR) AF: 0.000226 AC: 10 AN: 44182

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39360

South Asian (SAS) AF: 0.00987 AC: 842 AN: 85308

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53376

Middle Eastern (MID) AF: 0.00411 AC: 23 AN: 5598

European-Non Finnish (NFE) AF: 0.000233 AC: 259 AN: 1110430

Other (OTH) AF: 0.000581 AC: 35 AN: 60238

GnomAD4 genome AF: 0.000532 AC: 81 AN: 152334 Hom.: 0 Cov.: 32 AF XY: 0.000725 AC XY: 54 AN XY: 74486

African (AFR) AF: 0.000144 AC: 6 AN: 41576

American (AMR) AF: 0.000915 AC: 14 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00807 AC: 39 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000443 Hom.: 0

Bravo AF: 0.000325

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000386

EpiControl AF: 0.000599

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Sifrim-Hitz-Weiss syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	9.7
DANN	Benign	0.86
PhyloP100		3.5
PromoterAI		-0.023	Neutral
Mutation Taster		=94/6	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: rs201751048; hg19: chr12-6682268;