19-8510958-G-A

Variant names:

• chr19-8510958-G-A
• rs1177833260
• NM_001146175.2:c.992C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001146175.2(ZNF414):​c.992C>T​(p.Ala331Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000362 in 1,104,756 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A331D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000036 (1 hom.)
• Consequence: ZNF414 NM_001146175.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.46
• Publications: 0 publications found

Genes affected

ZNF414 (HGNC:20630): (zinc finger protein 414) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2641362).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF414	NM_001146175.2	c.992C>T	p.Ala331Val	missense_variant	Exon 7 of 8	ENST00000393927.9	NP_001139647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF414	ENST00000393927.9	c.992C>T	p.Ala331Val	missense_variant	Exon 7 of 8	1	NM_001146175.2	ENSP00000377504.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000362 AC: 4 AN: 1104756 Hom.: 1 Cov.: 32 AF XY: 0.00000760 AC XY: 4 AN XY: 526358

African (AFR) AF: 0.00 AC: 0 AN: 22988

American (AMR) AF: 0.000332 AC: 3 AN: 9046

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14760

East Asian (EAS) AF: 0.00 AC: 0 AN: 26478

South Asian (SAS) AF: 0.00 AC: 0 AN: 27754

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3128

European-Non Finnish (NFE) AF: 0.00000107 AC: 1 AN: 931836

Other (OTH) AF: 0.00 AC: 0 AN: 44436

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Benign	-0.11
Eigen_PC	Benign	0.061
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.1	T
PhyloP100		2.5
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.082
Sift	Benign	0.079	T
Sift4G	Benign	0.099	T
Vest4		0.25
MutPred		0.58		Gain of sheet (P = 0.0266);
MVP		0.46
MPC		0.40
ClinPred		0.94	D
GERP RS		4.5
gMVP		0.28
Mutation Taster		=95/5	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: rs1177833260; hg19: chr19-8575842;