19-7075651-C-G

Variant names:

• chr19-7075651-C-G
• rs75879765
• NM_024341.3:c.32-4C>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_024341.3(ZNF557):​c.32-4C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,613,188 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (5 hom.)
• Consequence: ZNF557 NM_024341.3 splice_region, intron
• Scores: Splicing: ADA: 0.0005705
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.240
• Publications: 1 publications found

Genes affected

ZNF557 (HGNC:28632): (zinc finger protein 557) Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in negative regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 5 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 19-7075651-C-G is Benign according to our data. Variant chr19-7075651-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2649149.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024341.3. 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
	ZNF557	NM_024341.3	MANE Select	c.32-4C>G		splice_region intron	N/A	NP_077317.2	Q8N988-2
	ZNF557	NM_001044387.2		c.32-4C>G		splice_region intron	N/A	NP_001037852.1	Q8N988-2
	ZNF557	NM_001044388.2		c.32-25C>G		intron	N/A	NP_001037853.1	Q8N988-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF557	ENST00000252840.11	TSL:1 MANE Select	c.32-4C>G		splice_region intron	N/A	ENSP00000252840.5	Q8N988-2
	ZNF557	ENST00000882902.1		c.32-4C>G		splice_region intron	N/A	ENSP00000552961.1
	ZNF557	ENST00000882905.1		c.32-4C>G		splice_region intron	N/A	ENSP00000552964.1

Frequencies

GnomAD3 genomes AF: 0.00173 AC: 264 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00228

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00204 AC: 513 AN: 251192 AF XY: 0.00208

Gnomad AFR exome AF: 0.000801

Gnomad AMR exome AF: 0.00541

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00220

Gnomad OTH exome AF: 0.00376

GnomAD4 exome AF: 0.00199 AC: 2903 AN: 1460890 Hom.: 5 Cov.: 31 AF XY: 0.00201 AC XY: 1462 AN XY: 726756

African (AFR) AF: 0.000359 AC: 12 AN: 33444

American (AMR) AF: 0.00548 AC: 245 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.000997 AC: 86 AN: 86236

European-Finnish (FIN) AF: 0.000187 AC: 10 AN: 53352

Middle Eastern (MID) AF: 0.00226 AC: 13 AN: 5760

European-Non Finnish (NFE) AF: 0.00215 AC: 2384 AN: 1111318

Other (OTH) AF: 0.00254 AC: 153 AN: 60330

GnomAD4 genome AF: 0.00172 AC: 262 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.00167 AC XY: 124 AN XY: 74470

African (AFR) AF: 0.000241 AC: 10 AN: 41560

American (AMR) AF: 0.00536 AC: 82 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00228 AC: 155 AN: 68022

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00221 Hom.: 0

Bravo AF: 0.00203

EpiCase AF: 0.00256

EpiControl AF: 0.00296

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	1.2
DANN	Benign	0.47
PhyloP100		-0.24
BranchPoint Hunter		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00057
dbscSNV1_RF	Benign	0.054
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: rs75879765; hg19: chr19-7075662;