9-37441713-G-T

Variant names:

• chr9-37441713-G-T
• rs756211364
• NM_014872.3:c.839C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014872.3(ZBTB5):​c.839C>A​(p.Ala280Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: ZBTB5 NM_014872.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.70

Genes affected

ZBTB5 (HGNC:23836): (zinc finger and BTB domain containing 5) Enables DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Involved in negative regulation of transcription by RNA polymerase II. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.055804998).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZBTB5	NM_014872.3	c.839C>A	p.Ala280Asp	missense_variant	Exon 2 of 2	ENST00000307750.5	NP_055687.1
ZBTB5	XM_005251634.3	c.839C>A	p.Ala280Asp	missense_variant	Exon 2 of 2		XP_005251691.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZBTB5	ENST00000307750.5	c.839C>A	p.Ala280Asp	missense_variant	Exon 2 of 2	1	NM_014872.3	ENSP00000307604.4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152064 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

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

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152064 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74274

Gnomad4 AFR AF: 0.0000241

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

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.839C>A (p.A280D) alteration is located in exon 2 (coding exon 1) of the ZBTB5 gene. This alteration results from a C to A substitution at nucleotide position 839, causing the alanine (A) at amino acid position 280 to be replaced by an aspartic acid (D). 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	Uncertain	0.34
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.0055	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.69	N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.039
Sift	Benign	0.043	D
Sift4G	Benign	0.19	T
Polyphen		0.0050	B
Vest4		0.13
MutPred		0.16		Gain of loop (P = 0.024);
MVP		0.043
MPC		0.36
ClinPred		0.10	T
GERP RS		2.8
Varity_R		0.12
gMVP		0.13

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: rs756211364; hg19: chr9-37441710;