10-30845215-C-T

Variant names:

• chr10-30845215-C-T
• rs140135024
• NM_001143768.2:c.2233G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001143768.2(ZNF438):​c.2233G>A​(p.Gly745Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,614,164 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.00064 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000060 (0 hom.)
• Consequence: ZNF438 NM_001143768.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.206
• Publications: 0 publications found

Genes affected

ZNF438 (HGNC:21029): (zinc finger protein 438) Enables DNA-binding transcription factor activity. Involved in negative regulation of transcription, DNA-templated. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0069302022).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001143768.2. 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
	ZNF438	NM_001143768.2	MANE Select	c.2233G>A	p.Gly745Arg	missense	Exon 7 of 7	NP_001137240.1	Q7Z4V0-1
	ZNF438	NM_001143766.2		c.2233G>A	p.Gly745Arg	missense	Exon 8 of 8	NP_001137238.1	Q7Z4V0-1
	ZNF438	NM_001143767.2		c.2233G>A	p.Gly745Arg	missense	Exon 6 of 6	NP_001137239.1	Q7Z4V0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF438	ENST00000436087.7	TSL:5 MANE Select	c.2233G>A	p.Gly745Arg	missense	Exon 7 of 7	ENSP00000406934.2	Q7Z4V0-1
	ZNF438	ENST00000361310.7	TSL:1	c.2233G>A	p.Gly745Arg	missense	Exon 7 of 7	ENSP00000354663.3	Q7Z4V0-1
	ZNF438	ENST00000331737.10	TSL:1	c.2203G>A	p.Gly735Arg	missense	Exon 8 of 8	ENSP00000333571.6	Q7Z4V0-2

Frequencies

GnomAD3 genomes AF: 0.000638 AC: 97 AN: 152152 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00225

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000143 AC: 36 AN: 251492 AF XY: 0.0000883

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.000116

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: 0.000163

GnomAD4 exome AF: 0.0000602 AC: 88 AN: 1461894 Hom.: 0 Cov.: 30 AF XY: 0.0000578 AC XY: 42 AN XY: 727248

African (AFR) AF: 0.00221 AC: 74 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.000116 AC: 7 AN: 60396

GnomAD4 genome AF: 0.000637 AC: 97 AN: 152270 Hom.: 1 Cov.: 32 AF XY: 0.000712 AC XY: 53 AN XY: 74452

African (AFR) AF: 0.00224 AC: 93 AN: 41542

American (AMR) AF: 0.000196 AC: 3 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000280 Hom.: 0

Bravo AF: 0.000801

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000189 AC: 23

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	0.12
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	4.8
DANN	Benign	0.60
DEOGEN2	Benign	0.0036	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.9	L
PhyloP100		-0.21
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.042
Sift	Benign	0.35	T
Sift4G	Benign	0.56	T
Polyphen		0.023	B
Vest4		0.11
MutPred		0.40		Gain of phosphorylation at S748 (P = 0.0772)
MVP		0.28
MPC		0.13
ClinPred		0.0089	T
GERP RS		1.4
Varity_R		0.035
gMVP		0.45
Mutation Taster		=98/2	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: rs140135024; hg19: chr10-31134144;