rs8373

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -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. Variant has been reported in ClinVar as (no stars).

• 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
• Publications: 37 publications found

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

Our verdict: Likely_benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001197051.2. 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
	ZFP91	NM_053023.5	MANE Select	c.619A>G	p.Ser207Gly	missense splice_region	Exon 5 of 11	NP_444251.1	Q96JP5-1
	ZFP91	NM_001197051.2		c.618-2A>G		splice_acceptor intron	N/A	NP_001183980.1
	ZFP91-CNTF	NR_024091.1		n.787A>G		splice_region non_coding_transcript_exon	Exon 5 of 13

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFP91	ENST00000316059.7	TSL:1 MANE Select	c.619A>G	p.Ser207Gly	missense splice_region	Exon 5 of 11	ENSP00000339030.5	Q96JP5-1
	ZFP91-CNTF	ENST00000389919.8	TSL:2	n.619A>G		splice_region non_coding_transcript_exon	Exon 5 of 13	ENSP00000455911.1
	ZFP91	ENST00000870367.1		c.619A>G	p.Ser207Gly	missense splice_region	Exon 6 of 12	ENSP00000540426.1

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

GnomAD2 exomes AF: 0.229 AC: 56179 AN: 245094 AF XY: 0.234

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 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

African (AFR) AF: 0.142 AC: 4744 AN: 33400

American (AMR) AF: 0.178 AC: 7943 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 6455 AN: 26084

East Asian (EAS) AF: 0.189 AC: 7471 AN: 39550

South Asian (SAS) AF: 0.259 AC: 22318 AN: 86028

European-Finnish (FIN) AF: 0.283 AC: 14552 AN: 51446

Middle Eastern (MID) AF: 0.298 AC: 1713 AN: 5756

European-Non Finnish (NFE) AF: 0.241 AC: 267702 AN: 1109874

Other (OTH) AF: 0.232 AC: 13964 AN: 60254

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

African (AFR) AF: 0.140 AC: 5800 AN: 41486

American (AMR) AF: 0.191 AC: 2915 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 907 AN: 3472

East Asian (EAS) AF: 0.182 AC: 945 AN: 5182

South Asian (SAS) AF: 0.275 AC: 1329 AN: 4824

European-Finnish (FIN) AF: 0.286 AC: 3026 AN: 10568

Middle Eastern (MID) AF: 0.360 AC: 105 AN: 292

European-Non Finnish (NFE) AF: 0.241 AC: 16372 AN: 67930

Other (OTH) AF: 0.217 AC: 456 AN: 2104

Alfa AF: 0.234 Hom.: 6787

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 v4.9

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
PhyloP100		3.6
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
Mutation Taster		=85/15	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8373; hg19: chr11-58378424; COSMIC: COSV60157968; COSMIC: COSV60157968;