11-65086423-C-T

Variant names:

• chr11-65086423-C-T
• NM_006782.4:c.223C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_006782.4(ZFPL1):​c.223C>T​(p.His75Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZFPL1 NM_006782.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.06

Genes affected

ZFPL1 (HGNC:12868): (zinc finger protein like 1) Predicted to enable metal ion binding activity. Predicted to be involved in vesicle-mediated transport. Located in Golgi apparatus. [provided by Alliance of Genome Resources, Apr 2022]

TMEM262 (HGNC:49389): (transmembrane protein 262) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFPL1	NM_006782.4	c.223C>T	p.His75Tyr	missense_variant	Exon 4 of 8	ENST00000294258.8	NP_006773.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFPL1	ENST00000294258.8	c.223C>T	p.His75Tyr	missense_variant	Exon 4 of 8	1	NM_006782.4	ENSP00000294258.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.223C>T (p.H75Y) alteration is located in exon 4 (coding exon 3) of the ZFPL1 gene. This alteration results from a C to T substitution at nucleotide position 223, causing the histidine (H) at amino acid position 75 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;T;T;T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Pathogenic	3.1	M;.;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.9	D;D;D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.97
MutPred		0.89		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;Loss of sheet (P = 0.0817);
MVP		0.83
MPC		1.0
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-64853895;