21-36413066-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005441.3(CHAF1B):c.1244C>T(p.Pro415Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000984 in 1,614,152 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0053 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (9 hom.)
• Consequence: CHAF1B NM_005441.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.246

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025869906).
• BP6: Variant 21-36413066-C-T is Benign according to our data. Variant chr21-36413066-C-T is described in ClinVar as [Benign]. Clinvar id is 730362.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00534 (813/152262) while in subpopulation AFR AF= 0.0182 (758/41560). AF 95% confidence interval is 0.0172. There are 5 homozygotes in gnomad4. There are 372 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHAF1B	NM_005441.3	c.1244C>T	p.Pro415Leu	missense_variant	12/14	ENST00000314103.6
CHAF1B	XM_047441000.1	c.683C>T	p.Pro228Leu	missense_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHAF1B	ENST00000314103.6	c.1244C>T	p.Pro415Leu	missense_variant	12/14	1	NM_005441.3	P1

Frequencies

GnomAD3 genomes AF: 0.00532 AC: 810 AN: 152144 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0182

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00132 AC: 331 AN: 251426 Hom.: 3 AF XY: 0.000883 AC XY: 120 AN XY: 135908

Gnomad AFR exome AF: 0.0182

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000531 AC: 776 AN: 1461890 Hom.: 9 Cov.: 31 AF XY: 0.000447 AC XY: 325 AN XY: 727246

Gnomad4 AFR exome AF: 0.0178

Gnomad4 AMR exome AF: 0.000872

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000459

Gnomad4 OTH exome AF: 0.00124

GnomAD4 genome AF: 0.00534 AC: 813 AN: 152262 Hom.: 5 Cov.: 32 AF XY: 0.00500 AC XY: 372 AN XY: 74444

Gnomad4 AFR AF: 0.0182

Gnomad4 AMR AF: 0.00249

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00160 Hom.: 1

Bravo AF: 0.00573

ESP6500AA AF: 0.0177 AC: 78

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00163 AC: 198

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	5.7
Dann	Benign	0.63
DEOGEN2	Benign	0.045	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.23	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.051
Sift	Benign	0.43	T
Sift4G	Benign	0.30	T
Polyphen		0.0010	B
Vest4		0.064
MVP		0.16
MPC		0.13
ClinPred		0.0065	T
GERP RS		-3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.014
gMVP		0.12

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: rs115050809; hg19: chr21-37785364; COSMIC: COSV58440673; COSMIC: COSV58440673;