chr12-42317822-C-T

Variant names:

• chr12-42317822-C-T
• rs977727528
• NM_033114.4:c.190G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_033114.4(ZCRB1):​c.190G>A​(p.Ala64Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,613,402 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 (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZCRB1 NM_033114.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.49
• Publications: 1 publications found

Genes affected

ZCRB1 (HGNC:29620): (zinc finger CCHC-type and RNA binding motif containing 1) Pre-mRNA splicing is catalyzed by the spliceosome. U12-type spliceosome binds U12-type pre-mRNAs and recognizes the 5' splice site and branch-point sequence. U11 and U12 snRNPs are components of U12-type spliceosome and function as a molecular bridge connecting both ends of the intron. The protein encoded by this gene contains a RNA recognition motif. It was identified as one of the protein components of U11/U12 snRNPs. This protein and many other U11/U12 snRNP proteins are highly conserved in organisms known to contain U12-type introns. These proteins have been shown to be essential for cell viability, suggesting the key roles in U12-type splicing. [provided by RefSeq, Jul 2008]

PPHLN1 (HGNC:19369): (periphilin 1) The protein encoded by this gene is one of the several proteins that become sequentially incorporated into the cornified cell envelope during the terminal differentiation of keratinocyte at the outer layers of epidermis. This protein interacts with periplakin, which is known as a precursor of the cornified cell envelope. The cellular localization pattern and insolubility of this protein suggest that it may play a role in epithelial differentiation and contribute to epidermal integrity and barrier formation. Multiple alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033114.4. 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
	ZCRB1	NM_033114.4	MANE Select	c.190G>A	p.Ala64Thr	missense	Exon 4 of 8	NP_149105.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZCRB1	ENST00000266529.8	TSL:1 MANE Select	c.190G>A	p.Ala64Thr	missense	Exon 4 of 8	ENSP00000266529.3	Q8TBF4
	ZCRB1	ENST00000552235.2	TSL:5	c.190G>A	p.Ala64Thr	missense	Exon 4 of 8	ENSP00000448780.2	F8VXY6
	ZCRB1	ENST00000677694.1		c.190G>A	p.Ala64Thr	missense	Exon 4 of 8	ENSP00000503171.1	Q8TBF4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152154 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461248 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726960

African (AFR) AF: 0.00 AC: 0 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5512

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111840

Other (OTH) AF: 0.00 AC: 0 AN: 60350

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152154 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74326

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00131091), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	0.99
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.16	T
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		5.5
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.16	T
Polyphen		0.99	D
Vest4		0.76
MutPred		0.77		Gain of phosphorylation at A64 (P = 0.0876)
MVP		0.70
MPC		0.86
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.60
gMVP		0.62
Mutation Taster		=45/55	disease causing

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: rs977727528; hg19: chr12-42711624; COSMIC: COSV56891332;