rs8373

Variant names:

• chr11-58610951-A-G
• rs8373
• NM_053023.5:c.619A>G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PVS1_Moderate BA1

The NM_001197051.2(ZFP91):​c.618-2A>G variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 1,609,072 control chromosomes in the GnomAD database, including 45,849 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.21 (3628 hom., cov: 32)
  • Exomes 𝑓: 0.24 (42221 hom.)
• Consequence: ZFP91 NM_001197051.2 splice_acceptor, intron
• Scores: Splicing: ADA: 0.8669
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.56

Genes affected

ZFP91 (HGNC:14983): (ZFP91 zinc finger protein, atypical E3 ubiquitin ligase) The protein encoded by this gene is a member of the zinc finger family of proteins. The gene product contains C2H2-type domains, which are the classical zinc finger domains found in numerous nucleic acid-binding proteins. This protein functions as a regulator of the non-canonical NF-kappaB pathway in lymphotoxin-beta receptor signaling. Alternative splicing results in multiple transcript variants. A read-through transcript variant composed of ZFP91 and the downstream CNTF gene sequence has been identified, but it is thought to be non-coding. Read-through transcription of ZFP91 and CNTF has also been observed in mouse. A ZFP91-related pseudogene has also been identified on chromosome 2. [provided by RefSeq, Oct 2010]

ZFP91-CNTF (HGNC:33441): (ZFP91-CNTF readthrough (NMD candidate)) This gene represents a read-through transcript composed of ZFP91 and CNTF sequence. This transcript is thought to be non-coding because it would be subject to nonsense-mediated mRNA decay (NMD). Read-through transcription of ZFP91 and CNTF has also been observed in mouse. [provided by RefSeq, Aug 2008]

ENSG00000269570 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.05964912 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.4, offset of -3, new splice context is: ttctatttacttatttttAGtgg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFP91	NM_053023.5	c.619A>G	p.Ser207Gly	missense_variant, splice_region_variant	Exon 5 of 11	ENST00000316059.7	NP_444251.1
ZFP91	NM_001197051.2	c.618-2A>G		splice_acceptor_variant, intron_variant	Intron 4 of 10		NP_001183980.1
ZFP91-CNTF	NR_024091.1	n.787A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFP91	ENST00000316059.7	c.619A>G	p.Ser207Gly	missense_variant, splice_region_variant	Exon 5 of 11	1	NM_053023.5	ENSP00000339030.5
ZFP91-CNTF	ENST00000389919.8	n.619A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 13	2		ENSP00000455911.1
ZFP91-CNTF	ENST00000422974.2	n.100A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 11	5		ENSP00000457288.1
ENSG00000269570	ENST00000601906.2	n.*168T>C		downstream_gene_variant		6

Frequencies

GnomAD3 genomes AF: 0.211 AC: 32084 AN: 151914 Hom.: 3623 Cov.: 32

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.267

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.261

Gnomad EAS AF: 0.182

Gnomad SAS AF: 0.277

Gnomad FIN AF: 0.286

Gnomad MID AF: 0.350

Gnomad NFE AF: 0.241

Gnomad OTH AF: 0.218

GnomAD3 exomes AF: 0.229 AC: 56179 AN: 245094 Hom.: 6834 AF XY: 0.234 AC XY: 31121 AN XY: 132898

Gnomad AFR exome AF: 0.139

Gnomad AMR exome AF: 0.174

Gnomad ASJ exome AF: 0.249

Gnomad EAS exome AF: 0.167

Gnomad SAS exome AF: 0.260

Gnomad FIN exome AF: 0.287

Gnomad NFE exome AF: 0.249

Gnomad OTH exome AF: 0.241

GnomAD4 exome AF: 0.238 AC: 346862 AN: 1457040 Hom.: 42221 Cov.: 30 AF XY: 0.239 AC XY: 173569 AN XY: 725000

Gnomad4 AFR exome AF: 0.142

Gnomad4 AMR exome AF: 0.178

Gnomad4 ASJ exome AF: 0.247

Gnomad4 EAS exome AF: 0.189

Gnomad4 SAS exome AF: 0.259

Gnomad4 FIN exome AF: 0.283

Gnomad4 NFE exome AF: 0.241

Gnomad4 OTH exome AF: 0.232

GnomAD4 genome AF: 0.211 AC: 32097 AN: 152032 Hom.: 3628 Cov.: 32 AF XY: 0.213 AC XY: 15854 AN XY: 74290

Gnomad4 AFR AF: 0.140

Gnomad4 AMR AF: 0.191

Gnomad4 ASJ AF: 0.261

Gnomad4 EAS AF: 0.182

Gnomad4 SAS AF: 0.275

Gnomad4 FIN AF: 0.286

Gnomad4 NFE AF: 0.241

Gnomad4 OTH AF: 0.217

Alfa AF: 0.241 Hom.: 5696

Bravo AF: 0.199

TwinsUK AF: 0.237 AC: 878

ALSPAC AF: 0.250 AC: 965

ESP6500AA AF: 0.143 AC: 631

ESP6500EA AF: 0.245 AC: 2108

ExAC AF: 0.234 AC: 28352

Asia WGS AF: 0.246 AC: 854 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.074	T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.10
Sift	Benign	0.045	D
Sift4G	Benign	0.41	T
Polyphen		0.92	P
Vest4		0.23
MPC		0.23
ClinPred		0.016	T
GERP RS		5.8
Varity_R		0.054
gMVP		0.069

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.87
dbscSNV1_RF	Pathogenic	0.74
SpliceAI score (max)		0.010		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: rs8373; hg19: chr11-58378424; COSMIC: COSV60157968; COSMIC: COSV60157968;