chr10-31502492-G-T

Variant names:

• chr10-31502492-G-T
• rs369587040
• NM_001174096.2:c.467G>T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_001323638.2(ZEB1):​c.-191G>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000328 in 1,613,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: ZEB1 NM_001323638.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.19

Genes affected

ZEB1 (HGNC:11642): (zinc finger E-box binding homeobox 1) This gene encodes a zinc finger transcription factor. The encoded protein likely plays a role in transcriptional repression of interleukin 2. Mutations in this gene have been associated with posterior polymorphous corneal dystrophy-3 and late-onset Fuchs endothelial corneal dystrophy. Alternatively spliced transcript variants encoding different isoforms have been described.[provided by RefSeq, Mar 2010]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20931262).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000138 (21/152266) while in subpopulation AFR AF= 0.000505 (21/41550). AF 95% confidence interval is 0.000338. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZEB1	NM_001174096.2	c.467G>T	p.Ser156Ile	missense_variant	Exon 4 of 9	ENST00000424869.6	NP_001167567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZEB1	ENST00000424869.6	c.467G>T	p.Ser156Ile	missense_variant	Exon 4 of 9	5	NM_001174096.2	ENSP00000415961.2

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000483

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000438 AC: 11 AN: 251258 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135776

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1461568 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 727080

Gnomad4 AFR exome AF: 0.000837

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74456

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000198 Hom.: 0

Bravo AF: 0.000181

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Oct 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.464G>T (p.S155I) alteration is located in exon 4 (coding exon 4) of the ZEB1 gene. This alteration results from a G to T substitution at nucleotide position 464, causing the serine (S) at amino acid position 155 to be replaced by an isoleucine (I). 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	Benign	0.24
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.36	T;.;.;T;.;.;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T;T;T;D;T;T;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.21	T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.8	L;.;.;.;.;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.3	N;N;N;D;N;N;D
REVEL	Uncertain	0.37
Sift	Benign	0.062	T;T;T;T;D;D;T
Sift4G	Benign	0.17	T;T;T;T;T;T;T
Polyphen		0.0030	B;.;.;.;.;.;.
Vest4		0.58
MVP		0.65
MPC		0.58
ClinPred		0.14	T
GERP RS		6.0
Varity_R		0.12
gMVP		0.45

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

Publications

LitVar

Other links and lift over

dbSNP: rs369587040; hg19: chr10-31791420;