chr21-36386183-T-C

Position:

• chr21-36386183-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP3 BP4_Strong BP6_Moderate BS2

The NM_005441.3(CHAF1B):​c.47T>C​(p.Val16Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00409 in 1,614,156 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (16 hom.)
• Consequence: CHAF1B NM_005441.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.58

Genes affected

CHAF1B (HGNC:1911): (chromatin assembly factor 1 subunit B) Chromatin assembly factor I (CAF-I) is required for the assembly of histone octamers onto newly-replicated DNA. CAF-I is composed of three protein subunits, p50, p60, and p150. The protein encoded by this gene corresponds to the p60 subunit and is required for chromatin assembly after replication. The encoded protein is differentially phosphorylated in a cell cycle-dependent manner. In addition, it is normally found in the nucleus except during mitosis, when it is released into the cytoplasm. This protein is a member of the WD-repeat HIR1 family and may also be involved in DNA repair. [provided by RefSeq, Jul 2008]

CHAF1B (HGNC:):

MORC3 (HGNC:23572): (MORC family CW-type zinc finger 3) This gene encodes a protein that localizes to the nuclear matrix and forms nuclear bodies via an ATP-dependent mechanism. The protein is predicted to have coiled-coil and zinc finger domains and has RNA binding activity. Alternative splicing produces multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.027602911).
• BP6: Variant 21-36386183-T-C is Benign according to our data. Variant chr21-36386183-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2652647.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHAF1B	NM_005441.3	c.47T>C	p.Val16Ala	missense_variant	2/14	ENST00000314103.6	NP_005432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHAF1B	ENST00000314103.6	c.47T>C	p.Val16Ala	missense_variant	2/14	1	NM_005441.3	ENSP00000315700.4

Frequencies

GnomAD3 genomes AF: 0.00273 AC: 416 AN: 152186 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00463

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00281 AC: 706 AN: 251436 Hom.: 2 AF XY: 0.00274 AC XY: 372 AN XY: 135880

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00476

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000751

Gnomad FIN exome AF: 0.00185

Gnomad NFE exome AF: 0.00446

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00423 AC: 6180 AN: 1461852 Hom.: 16 Cov.: 30 AF XY: 0.00403 AC XY: 2931 AN XY: 727238

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.00417

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00104

Gnomad4 FIN exome AF: 0.00198

Gnomad4 NFE exome AF: 0.00495

Gnomad4 OTH exome AF: 0.00407

GnomAD4 genome AF: 0.00273 AC: 416 AN: 152304 Hom.: 2 Cov.: 32 AF XY: 0.00251 AC XY: 187 AN XY: 74474

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00463

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00420 Hom.: 1

Bravo AF: 0.00265

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00535 AC: 46

ExAC AF: 0.00276 AC: 335

EpiCase AF: 0.00469

EpiControl AF: 0.00368

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

CHAF1B: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.028	T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Pathogenic	3.7	H
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.83
MVP		0.81
MPC		1.9
ClinPred		0.096	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs143543321; hg19: chr21-37758481;