14-73903972-A-C

Position:

• chr14-73903972-A-C

Variant summary

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

The NM_021188.3(ZNF410):​c.593A>C​(p.His198Pro) 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: 32)
• Consequence: ZNF410 NM_021188.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.52

Genes affected

ZNF410 (HGNC:20144): (zinc finger protein 410) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

(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	UniProt
ZNF410	NM_021188.3	c.593A>C	p.His198Pro	missense_variant	6/12	ENST00000555044.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF410	ENST00000555044.6	c.593A>C	p.His198Pro	missense_variant	6/12	1	NM_021188.3	P1
	ENST00000554009.1	n.65-7404T>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251370 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135850

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

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

Aug 10, 2023

The c.644A>C (p.H215P) alteration is located in exon 7 (coding exon 6) of the ZNF410 gene. This alteration results from a A to C substitution at nucleotide position 644, causing the histidine (H) at amino acid position 215 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	Benign	0.19
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;.;D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.51	D;D;D;D;D;D
MetaSVM	Benign	-0.75	T
MutationTaster	Benign	1.0	D;D;D;D;D;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.8	D;D;D;D;D;.
REVEL	Benign	0.20
Sift	Uncertain	0.0020	D;D;D;D;D;.
Sift4G	Uncertain	0.010	D;D;D;D;D;D
Polyphen		0.99, 0.98	.;D;.;D;.;.
Vest4		0.69
MutPred		0.43		.;Gain of loop (P = 0.0195);.;Gain of loop (P = 0.0195);.;.;
MVP		0.29
MPC		1.5
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.52
gMVP		0.58

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: rs768415927; hg19: chr14-74370675;