7-1157699-T-C

Variant names:

• chr7-1157699-T-C
• rs1358292928
• NM_182491.4:c.107A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_182491.4(ZFAND2A):​c.107A>G​(p.His36Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000142 in 1,413,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H36Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZFAND2A NM_182491.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.13
• Publications: 0 publications found

Genes affected

ZFAND2A (HGNC:28073): (zinc finger AN1-type containing 2A) Predicted to enable zinc ion binding activity. Predicted to be involved in proteasome-mediated ubiquitin-dependent protein catabolic process and protein targeting to ER. Predicted to act upstream of or within cellular response to arsenic-containing substance and positive regulation of proteasomal ubiquitin-dependent protein catabolic process. Predicted to be located in nucleus. Predicted to be part of proteasome complex. Predicted to be active in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity ZFN2A_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182491.4. 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
	ZFAND2A	NM_182491.4	MANE Select	c.107A>G	p.His36Arg	missense	Exon 3 of 5	NP_872297.2	Q8N6M9
	ZFAND2A	NM_001365383.1		c.107A>G	p.His36Arg	missense	Exon 3 of 6	NP_001352312.1	J3KQ25
	ZFAND2A	NM_001365381.2		c.107A>G	p.His36Arg	missense	Exon 3 of 5	NP_001352310.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFAND2A	ENST00000316495.8	TSL:1 MANE Select	c.107A>G	p.His36Arg	missense	Exon 3 of 5	ENSP00000314619.3	Q8N6M9
	ZFAND2A	ENST00000397083.6	TSL:1	c.107A>G	p.His36Arg	missense	Exon 3 of 5	ENSP00000380273.1	A8MYA3
	ZFAND2A	ENST00000401903.6	TSL:3	c.107A>G	p.His36Arg	missense	Exon 3 of 6	ENSP00000386031.1	J3KQ25

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000463 AC: 1 AN: 215862 AF XY: 0.00000849

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000951

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1413186 Hom.: 0 Cov.: 30 AF XY: 0.00000286 AC XY: 2 AN XY: 699602

African (AFR) AF: 0.00 AC: 0 AN: 30824

American (AMR) AF: 0.00 AC: 0 AN: 30822

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24490

East Asian (EAS) AF: 0.00 AC: 0 AN: 38566

South Asian (SAS) AF: 0.00 AC: 0 AN: 78966

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53054

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5650

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1092468

Other (OTH) AF: 0.00 AC: 0 AN: 58346

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000378

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	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H
PhyloP100		7.1
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.81		Loss of catalytic residue at F37 (P = 0.0696)
MVP		0.97
MPC		0.051
ClinPred		1.0	D
GERP RS		5.3
PromoterAI		-0.013	Neutral
Varity_R		0.95
gMVP		0.66
Mutation Taster		=56/44	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: rs1358292928; hg19: chr7-1197335;