19-51896525-T-G

Position:

• chr19-51896525-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_023074.4(ZNF649):​c.185A>C​(p.Gln62Pro) 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF649 NM_023074.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.83

Genes affected

ZNF649 (HGNC:25741): (zinc finger protein 649) Predicted to enable DNA-binding transcription factor activity and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to act upstream of or within negative regulation of transcription, DNA-templated. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF649-AS1 (HGNC:51285): (ZNF649 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1773571).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF649	NM_023074.4	c.185A>C	p.Gln62Pro	missense_variant	4/5	ENST00000354957.8	NP_075562.2
ZNF649-AS1	NR_110733.1	n.238+229T>G		intron_variant, non_coding_transcript_variant
ZNF649	XM_047439238.1	c.173A>C	p.Gln58Pro	missense_variant	4/5		XP_047295194.1
ZNF649	XM_047439239.1	c.-251A>C		5_prime_UTR_variant	2/3		XP_047295195.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF649	ENST00000354957.8	c.185A>C	p.Gln62Pro	missense_variant	4/5	1	NM_023074.4	ENSP00000347043	P1
ZNF649	ENST00000600738.5	c.185A>C	p.Gln62Pro	missense_variant	4/6	1		ENSP00000468983
ZNF649-AS1	ENST00000600329.1	n.238+229T>G		intron_variant, non_coding_transcript_variant		4
ZNF649	ENST00000599671.1	n.411A>C		non_coding_transcript_exon_variant	2/2	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Feb 07, 2023

The c.185A>C (p.Q62P) alteration is located in exon 4 (coding exon 3) of the ZNF649 gene. This alteration results from a A to C substitution at nucleotide position 185, causing the glutamine (Q) at amino acid position 62 to be replaced by a proline (P). 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	Uncertain	0.40
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	4.1
DANN	Benign	0.71
DEOGEN2	Benign	0.057	T;T
Eigen	Benign	-0.84
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.42	T;T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-3.5	D;.
REVEL	Benign	0.099
Sift	Uncertain	0.0040	D;.
Sift4G	Uncertain	0.035	D;D
Polyphen		0.98	D;.
Vest4		0.30
MutPred		0.42		Gain of disorder (P = 0.1202);Gain of disorder (P = 0.1202);
MVP		0.33
MPC		0.20
ClinPred		0.38	T
GERP RS		-3.8
Varity_R		0.24
gMVP		0.51

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: chr19-52399778;