1-182056575-G-A

Variant names:

• chr1-182056575-G-A
• rs200671620
• NM_001009992.1:c.1436C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001009992.1(ZNF648):​c.1436C>T​(p.Thr479Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000616 in 1,614,064 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T479R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00056 (5 hom.)
• Consequence: ZNF648 NM_001009992.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.122
• Publications: 4 publications found

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]

ENSG00000225982 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0049058497).
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001009992.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF648	NM_001009992.1	MANE Select	c.1436C>T	p.Thr479Met	missense	Exon 2 of 2	NP_001009992.1	Q5T619

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF648	ENST00000339948.3	TSL:1 MANE Select	c.1436C>T	p.Thr479Met	missense	Exon 2 of 2	ENSP00000344129.3	Q5T619
	ZNF648	ENST00000673963.1		c.881C>T	p.Thr294Met	missense	Exon 2 of 2	ENSP00000501285.1	A0A669KBK7
	ENSG00000225982	ENST00000756799.1		n.154+26976G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 176 AN: 152276 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0136

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000411

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00135 AC: 336 AN: 249730 AF XY: 0.00135

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0136

Gnomad NFE exome AF: 0.000266

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.000560 AC: 819 AN: 1461670 Hom.: 5 Cov.: 31 AF XY: 0.000551 AC XY: 401 AN XY: 727114

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86214

European-Finnish (FIN) AF: 0.0134 AC: 716 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000567 AC: 63 AN: 1111926

Other (OTH) AF: 0.000530 AC: 32 AN: 60388

GnomAD4 genome AF: 0.00115 AC: 176 AN: 152394 Hom.: 0 Cov.: 33 AF XY: 0.00184 AC XY: 137 AN XY: 74524

African (AFR) AF: 0.00 AC: 0 AN: 41602

American (AMR) AF: 0.0000653 AC: 1 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.0136 AC: 145 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68040

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000338 Hom.: 1

Bravo AF: 0.0000982

ExAC AF: 0.00128 AC: 156

EpiCase AF: 0.0000545

EpiControl AF: 0.0000594

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0079	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.27	N
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.12
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.085
Sift	Benign	0.054	T
Sift4G	Benign	0.10	T
Polyphen		0.30	B
Vest4		0.25
MVP		0.061
MPC		0.99
ClinPred		0.070	T
GERP RS		2.8
Varity_R		0.026
gMVP		0.082
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs200671620; hg19: chr1-182025710; COSMIC: COSV60571157;