rs749670

chr16-31077304-A-Gchr16-31077304-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014699.4(ZNF646):c.980A>G(p.Glu327Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 1,612,972 control chromosomes in the GnomAD database, including 125,382 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.31 (9906 hom., cov: 33)
  • Exomes 𝑓: 0.38 (115476 hom.)
• Consequence: ZNF646 NM_014699.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.126

Genes affected

ZNF646 (HGNC:29004): (zinc finger protein 646) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription, DNA-templated. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.00967E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.869 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF646	NM_014699.4	c.980A>G	p.Glu327Gly	missense_variant	2/3	ENST00000300850.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF646	ENST00000300850.5	c.980A>G	p.Glu327Gly	missense_variant	2/3	1	NM_014699.4	P2
ZNF646	ENST00000394979.2	c.980A>G	p.Glu327Gly	missense_variant	1/1			A2

Frequencies

GnomAD3 genomes AF: 0.312 AC: 47383 AN: 152058 Hom.: 9905 Cov.: 33

Gnomad AFR AF: 0.0739

Gnomad AMI AF: 0.441

Gnomad AMR AF: 0.388

Gnomad ASJ AF: 0.499

Gnomad EAS AF: 0.890

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.390

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.378

Gnomad OTH AF: 0.382

GnomAD3 exomes AF: 0.395 AC: 98241 AN: 248600 Hom.: 23403 AF XY: 0.386 AC XY: 51906 AN XY: 134532

Gnomad AFR exome AF: 0.0664

Gnomad AMR exome AF: 0.456

Gnomad ASJ exome AF: 0.488

Gnomad EAS exome AF: 0.893

Gnomad SAS exome AF: 0.181

Gnomad FIN exome AF: 0.383

Gnomad NFE exome AF: 0.394

Gnomad OTH exome AF: 0.406

GnomAD4 exome AF: 0.380 AC: 555213 AN: 1460796 Hom.: 115476 Cov.: 76 AF XY: 0.376 AC XY: 273013 AN XY: 726656

Gnomad4 AFR exome AF: 0.0645

Gnomad4 AMR exome AF: 0.454

Gnomad4 ASJ exome AF: 0.490

Gnomad4 EAS exome AF: 0.903

Gnomad4 SAS exome AF: 0.185

Gnomad4 FIN exome AF: 0.390

Gnomad4 NFE exome AF: 0.379

Gnomad4 OTH exome AF: 0.389

GnomAD4 genome AF: 0.311 AC: 47383 AN: 152176 Hom.: 9906 Cov.: 33 AF XY: 0.314 AC XY: 23364 AN XY: 74388

Gnomad4 AFR AF: 0.0738

Gnomad4 AMR AF: 0.389

Gnomad4 ASJ AF: 0.499

Gnomad4 EAS AF: 0.891

Gnomad4 SAS AF: 0.178

Gnomad4 FIN AF: 0.390

Gnomad4 NFE AF: 0.378

Gnomad4 OTH AF: 0.380

Alfa AF: 0.391 Hom.: 15313

Bravo AF: 0.314

TwinsUK AF: 0.371 AC: 1374

ALSPAC AF: 0.367 AC: 1416

ESP6500AA AF: 0.0892 AC: 392

ESP6500EA AF: 0.403 AC: 3462

ExAC AF: 0.381 AC: 46216

Asia WGS AF: 0.456 AC: 1589 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	12
Dann	Benign	0.97
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.44	T;T
MetaRNN	Benign	7.0e-7	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.17	N;N
REVEL	Benign	0.14
Sift	Benign	0.12	T;T
Sift4G	Benign	0.17	T;T
Polyphen		0.019	B;.
Vest4		0.097
MPC		0.39
ClinPred		0.0048	T
GERP RS		4.2
Varity_R		0.037
gMVP		0.63

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: rs749670; hg19: chr16-31088625; COSMIC: COSV56212783; COSMIC: COSV56212783;