19-12044724-G-T

Position:

• chr19-12044724-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001080404.3(ZNF878):​c.677C>A​(p.Pro226His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF878 NM_001080404.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.35

Genes affected

ZNF878 (HGNC:37246): (zinc finger protein 878) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF433-AS1 (HGNC:53776): (ZNF433 and ZNF878 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39762196).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF878	NM_001080404.3	c.677C>A	p.Pro226His	missense_variant	4/4	ENST00000547628.2	NP_001073873.2
ZNF433-AS1	NR_134928.1	n.476-1358G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF878	ENST00000547628.2	c.677C>A	p.Pro226His	missense_variant	4/4	3	NM_001080404.3	ENSP00000447931	P1
ZNF433-AS1	ENST00000476474.5	n.414-1358G>T		intron_variant, non_coding_transcript_variant		2
ZNF433-AS1	ENST00000591838.5	n.237-1358G>T		intron_variant, non_coding_transcript_variant		5
ZNF433-AS1	ENST00000591898.1	n.163-1358G>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 14, 2024

The c.677C>A (p.P226H) alteration is located in exon 4 (coding exon 4) of the ZNF878 gene. This alteration results from a C to A substitution at nucleotide position 677, causing the proline (P) at amino acid position 226 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Benign	0.18
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.0049	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	0.66	D
PrimateAI	Benign	0.32	T
PROVEAN	Pathogenic	-8.3	D
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.24
MutPred		0.42		Gain of MoRF binding (P = 0.081);
MVP		0.42
MPC		0.82
ClinPred		1.0	D
GERP RS		0.75
Varity_R		0.69
gMVP		0.037

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-12155539;