chr1-182057301-G-T

Position:

• chr1-182057301-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000339948.3(ZNF648):​c.710C>A​(p.Ala237Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ZNF648 ENST00000339948.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.766

Genes affected

ZNF648 (HGNC:18190): (zinc finger protein 648) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription, DNA-templated. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.038179845).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF648	NM_001009992.1	c.710C>A	p.Ala237Glu	missense_variant	2/2	ENST00000339948.3	NP_001009992.1
ZNF648	XM_024453260.2	c.710C>A	p.Ala237Glu	missense_variant	3/3		XP_024309028.1
ZNF648	XM_047445722.1	c.710C>A	p.Ala237Glu	missense_variant	4/4		XP_047301678.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF648	ENST00000339948.3	c.710C>A	p.Ala237Glu	missense_variant	2/2	1	NM_001009992.1	ENSP00000344129.3
ZNF648	ENST00000673963.1	c.155C>A	p.Ala52Glu	missense_variant	2/2			ENSP00000501285.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449230 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 721082

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Apr 27, 2022

The c.710C>A (p.A237E) alteration is located in exon 2 (coding exon 1) of the ZNF648 gene. This alteration results from a C to A substitution at nucleotide position 710, causing the alanine (A) at amino acid position 237 to be replaced by a glutamic acid (E). 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	Benign	0.11
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.015
DANN	Benign	0.61
DEOGEN2	Benign	0.0031	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.85	L
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.0020
Sift	Benign	0.23	T
Sift4G	Benign	0.89	T
Polyphen		0.014	B
Vest4		0.044
MutPred		0.32		Gain of methylation at K232 (P = 0.0611);
MVP		0.030
MPC		0.45
ClinPred		0.063	T
GERP RS		-3.6
Varity_R		0.072
gMVP		0.25

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: chr1-182026436;