1-200407966-T-C

Variant names:

• chr1-200407966-T-C
• rs61734668
• NM_001281293.2:c.1740A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001281293.2(ZNF281):​c.1740A>G​(p.Pro580Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00339 in 1,614,218 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (69 hom.)
• Consequence: ZNF281 NM_001281293.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.80
• Publications: 3 publications found

Genes affected

ZNF281 (HGNC:13075): (zinc finger protein 281) Enables DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Involved in negative regulation of gene expression; negative regulation of transcription by RNA polymerase II; and positive regulation of transcription, DNA-templated. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000230623 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-200407966-T-C is Benign according to our data. Variant chr1-200407966-T-C is described in ClinVar as Benign. ClinVar VariationId is 711738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00248 (378/152348) while in subpopulation SAS AF = 0.0259 (125/4832). AF 95% confidence interval is 0.0222. There are 6 homozygotes in GnomAd4. There are 210 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 378 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001281293.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF281	NM_001281293.2	MANE Select	c.1740A>G	p.Pro580Pro	synonymous	Exon 2 of 2	NP_001268222.1	Q9Y2X9-1
	ZNF281	NM_012482.5		c.1740A>G	p.Pro580Pro	synonymous	Exon 2 of 2	NP_036614.1	Q9Y2X9-1
	ZNF281	NM_001281294.2		c.1632A>G	p.Pro544Pro	synonymous	Exon 3 of 3	NP_001268223.1	Q9Y2X9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF281	ENST00000367353.2	TSL:1 MANE Select	c.1740A>G	p.Pro580Pro	synonymous	Exon 2 of 2	ENSP00000356322.1	Q9Y2X9-1
	ZNF281	ENST00000294740.3	TSL:1	c.1740A>G	p.Pro580Pro	synonymous	Exon 2 of 2	ENSP00000294740.2	Q9Y2X9-1
	ZNF281	ENST00000890708.1		c.1740A>G	p.Pro580Pro	synonymous	Exon 2 of 2	ENSP00000560767.1

Frequencies

GnomAD3 genomes AF: 0.00248 AC: 378 AN: 152230 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0258

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.00187

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.00537 AC: 1349 AN: 251294 AF XY: 0.00665

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.0120

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00235

Gnomad OTH exome AF: 0.00880

GnomAD4 exome AF: 0.00349 AC: 5100 AN: 1461870 Hom.: 69 Cov.: 33 AF XY: 0.00435 AC XY: 3165 AN XY: 727236

African (AFR) AF: 0.000926 AC: 31 AN: 33480

American (AMR) AF: 0.00179 AC: 80 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0116 AC: 303 AN: 26130

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39696

South Asian (SAS) AF: 0.0282 AC: 2434 AN: 86258

European-Finnish (FIN) AF: 0.000412 AC: 22 AN: 53414

Middle Eastern (MID) AF: 0.0354 AC: 204 AN: 5768

European-Non Finnish (NFE) AF: 0.00150 AC: 1671 AN: 1112008

Other (OTH) AF: 0.00575 AC: 347 AN: 60394

GnomAD4 genome AF: 0.00248 AC: 378 AN: 152348 Hom.: 6 Cov.: 32 AF XY: 0.00282 AC XY: 210 AN XY: 74496

African (AFR) AF: 0.000361 AC: 15 AN: 41584

American (AMR) AF: 0.00261 AC: 40 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 37 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5186

South Asian (SAS) AF: 0.0259 AC: 125 AN: 4832

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.00187 AC: 127 AN: 68036

Other (OTH) AF: 0.00758 AC: 16 AN: 2112

Alfa AF: 0.00285 Hom.: 3

Bravo AF: 0.00199

Asia WGS AF: 0.00953 AC: 33 AN: 3478

EpiCase AF: 0.00294

EpiControl AF: 0.00409

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.9
DANN	Benign	0.41
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs61734668; hg19: chr1-200377094; COSMIC: COSV99664621; COSMIC: COSV99664621;