19-44229793-T-C

Variant names:

• chr19-44229793-T-C
• rs938535314
• NM_182490.3:c.248T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_182490.3(ZNF227):​c.248T>C​(p.Met83Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000632 in 1,583,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: ZNF227 NM_182490.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.146
• Publications: 0 publications found

Genes affected

ZNF227 (HGNC:13020): (zinc finger protein 227) Predicted to enable DNA-binding transcription activator 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 by RNA polymerase II. Predicted to act upstream of or within negative regulation of transcription, DNA-templated. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF235 (HGNC:12866): (zinc finger protein 235) This gene product belongs to the zinc finger protein superfamily, members of which are regulatory proteins characterized by nucleic acid-binding zinc finger domains. The encoded protein is a member of the Kruppel family of zinc finger proteins, and contains Kruppel-associated box (KRAB) A and B domains and 15 tandemly arrayed C2H2-type zinc fingers. It is an ortholog of the mouse Zfp93 protein. This gene is located in a cluster of zinc finger genes on 19q13.2. [provided by RefSeq, Jul 2008]

LOC124904726 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.036284775).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182490.3. 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
	ZNF227	NM_182490.3	MANE Select	c.248T>C	p.Met83Thr	missense	Exon 5 of 6	NP_872296.1	Q86WZ6-1
	ZNF227	NM_001289166.2		c.248T>C	p.Met83Thr	missense	Exon 5 of 6	NP_001276095.1	Q86WZ6-1
	ZNF227	NM_001289167.2		c.95T>C	p.Met32Thr	missense	Exon 5 of 6	NP_001276096.1	Q86WZ6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF227	ENST00000313040.12	TSL:1 MANE Select	c.248T>C	p.Met83Thr	missense	Exon 5 of 6	ENSP00000321049.6	Q86WZ6-1
	ZNF227	ENST00000621083.4	TSL:2	c.248T>C	p.Met83Thr	missense	Exon 5 of 6	ENSP00000482749.1	Q86WZ6-1
	ZNF227	ENST00000876872.1		c.248T>C	p.Met83Thr	missense	Exon 5 of 6	ENSP00000546931.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000811 AC: 2 AN: 246754 AF XY: 0.00

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000419 AC: 6 AN: 1431234 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 711584

African (AFR) AF: 0.000181 AC: 6 AN: 33064

American (AMR) AF: 0.00 AC: 0 AN: 44050

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25238

East Asian (EAS) AF: 0.00 AC: 0 AN: 39216

South Asian (SAS) AF: 0.00 AC: 0 AN: 81984

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51910

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5584

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1091654

Other (OTH) AF: 0.00 AC: 0 AN: 58534

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74352

African (AFR) AF: 0.0000965 AC: 4 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000416

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	16
DANN	Benign	0.82
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0014	T
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.15
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.19
Sift	Benign	0.081	T
Sift4G	Uncertain	0.055	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.31		Loss of phosphorylation at T88 (P = 0.1073)
MVP		0.040
MPC		0.11
ClinPred		0.011	T
GERP RS		-1.3
Varity_R		0.055
gMVP		0.042
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs938535314; hg19: chr19-44733946;