chr10-30845350-C-T

Variant names:

• chr10-30845350-C-T
• rs745945796
• NM_001143768.2:c.2098G>A

Variant summary

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

The NM_001143768.2(ZNF438):​c.2098G>A​(p.Asp700Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,613,990 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 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: ZNF438 NM_001143768.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.758
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.043165326).

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.2098G>A	p.Asp700Asn	missense	Exon 7 of 7	NP_001137240.1	Q7Z4V0-1
	ZNF438	NM_001143766.2		c.2098G>A	p.Asp700Asn	missense	Exon 8 of 8	NP_001137238.1	Q7Z4V0-1
	ZNF438	NM_001143767.2		c.2098G>A	p.Asp700Asn	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.2098G>A	p.Asp700Asn	missense	Exon 7 of 7	ENSP00000406934.2	Q7Z4V0-1
	ZNF438	ENST00000361310.7	TSL:1	c.2098G>A	p.Asp700Asn	missense	Exon 7 of 7	ENSP00000354663.3	Q7Z4V0-1
	ZNF438	ENST00000331737.10	TSL:1	c.2068G>A	p.Asp690Asn	missense	Exon 8 of 8	ENSP00000333571.6	Q7Z4V0-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152096 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000278 AC: 7 AN: 251488 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727248

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 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: 0.00000360 AC: 4 AN: 1112012

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152096 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74306

African (AFR) AF: 0.00 AC: 0 AN: 41398

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10594

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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	0.073
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.9
DANN	Benign	0.94
DEOGEN2	Benign	0.0016	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.76
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.021
Sift	Benign	0.28	T
Sift4G	Benign	0.083	T
Polyphen		0.32	B
Vest4		0.042
MutPred		0.27		Gain of MoRF binding (P = 0.0316)
MVP		0.43
MPC		0.066
ClinPred		0.027	T
GERP RS		-1.7
Varity_R		0.041
gMVP		0.19
Mutation Taster		=99/1	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: rs745945796; hg19: chr10-31134279; COSMIC: COSV100062940;