1-40462478-A-G

Variant names:

• chr1-40462478-A-G
• rs149532463
• NM_023070.3:c.494A>G

Variant summary

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

The NM_023070.3(ZFP69B):​c.494A>G​(p.Glu165Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000321 in 1,612,670 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (1 hom.)
• Consequence: ZFP69B NM_023070.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.604

Genes affected

ZFP69B (HGNC:28053): (ZFP69 zinc finger protein B) Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Involved in Golgi organization. Located in nucleolus. [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=0.0089301765).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFP69B	NM_023070.3	c.494A>G	p.Glu165Gly	missense_variant	Exon 5 of 5	ENST00000361584.5	NP_075558.2
ZFP69B	NM_001369565.1	c.494A>G	p.Glu165Gly	missense_variant	Exon 6 of 6		NP_001356494.1
ZFP69B	XM_005271136.2	c.497A>G	p.Glu166Gly	missense_variant	Exon 6 of 6		XP_005271193.1
ZFP69B	XM_017002147.2	c.497A>G	p.Glu166Gly	missense_variant	Exon 6 of 6		XP_016857636.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFP69B	ENST00000361584.5	c.494A>G	p.Glu165Gly	missense_variant	Exon 5 of 5	1	NM_023070.3	ENSP00000354547.4
ZFP69B	ENST00000484445.5	c.*12A>G		3_prime_UTR_variant	Exon 5 of 5	1		ENSP00000435907.1
ZFP69B	ENST00000411995.6	c.494A>G	p.Glu165Gly	missense_variant	Exon 6 of 6	5		ENSP00000399664.2
ZFP69B	ENST00000469416.1	n.1146A>G		non_coding_transcript_exon_variant	Exon 5 of 5	2

Frequencies

GnomAD3 genomes AF: 0.000282 AC: 43 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00987

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: 0.000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000160 AC: 40 AN: 249412 Hom.: 0 AF XY: 0.000163 AC XY: 22 AN XY: 134744

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.0000585

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: 0.000319

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000325 AC: 475 AN: 1460332 Hom.: 1 Cov.: 32 AF XY: 0.000319 AC XY: 232 AN XY: 726330

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.0000451

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: 0.000410

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74504

Gnomad4 AFR AF: 0.0000962

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: 0.000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000343 Hom.: 0

Bravo AF: 0.000314

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000327

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.494A>G (p.E165G) alteration is located in exon 5 (coding exon 5) of the ZFP69B gene. This alteration results from a A to G substitution at nucleotide position 494, causing the glutamic acid (E) at amino acid position 165 to be replaced by a glycine (G). 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	0.097
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.030	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.000020	N
LIST_S2	Benign	0.49	.;T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.0089	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.7	M;M
PrimateAI	Benign	0.24	T
PROVEAN	Pathogenic	-4.5	D;.
REVEL	Benign	0.026
Sift	Benign	0.076	T;.
Sift4G	Benign	0.097	T;T
Polyphen		0.0020	B;B
Vest4		0.12
MVP		0.072
MPC		0.11
ClinPred		0.13	T
GERP RS		0.99
Varity_R		0.15
gMVP		0.12

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: rs149532463; hg19: chr1-40928150;