10-37831674-A-G

Position:

• chr10-37831674-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_021045.3(ZNF248):​c.1681T>C​(p.Ser561Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZNF248 NM_021045.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.03

Genes affected

ZNF248 (HGNC:13041): (zinc finger protein 248) Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in negative regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF248 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF248	NM_021045.3	c.1681T>C	p.Ser561Pro	missense_variant	6/6	ENST00000395867.8	NP_066383.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF248	ENST00000395867.8	c.1681T>C	p.Ser561Pro	missense_variant	6/6	1	NM_021045.3	ENSP00000379208.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251002 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135658

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

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

Sep 29, 2023

The c.1681T>C (p.S561P) alteration is located in exon 6 (coding exon 4) of the ZNF248 gene. This alteration results from a T to C substitution at nucleotide position 1681, causing the serine (S) at amino acid position 561 to be replaced by a proline (P). 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	Pathogenic	0.94
BayesDel_addAF	Benign	0.0029	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;T
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.71	.;T
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Benign	0.16
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	D;D
Vest4		0.56
MutPred		0.60		Loss of catalytic residue at S561 (P = 0.0381);Loss of catalytic residue at S561 (P = 0.0381);
MVP		0.69
MPC		0.60
ClinPred		0.97	D
GERP RS		3.3
Varity_R		0.61
gMVP		0.42

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

LitVar

Other links and lift over

dbSNP: rs1277311202; hg19: chr10-38120602;