chr4-25312898-C-T

Variant names:

• chr4-25312898-C-T
• rs61743521
• NM_024936.3:c.89C>T

Variant summary

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

The NM_024936.3(ZCCHC4):​c.89C>T​(p.Pro30Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,612,906 control chromosomes in the GnomAD database, including 59 homozygotes. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (31 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (28 hom.)
• Consequence: ZCCHC4 NM_024936.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.147
• Publications: 2 publications found

Genes affected

ZCCHC4 (HGNC:22917): (zinc finger CCHC-type containing 4) Enables S-adenosyl-L-methionine binding activity; rRNA (adenine-N6-)-methyltransferase activity; and zinc ion binding activity. Involved in positive regulation of translation and rRNA methylation. Located in cytoplasm and nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030532181).
• BP6: Variant 4-25312898-C-T is Benign according to our data. Variant chr4-25312898-C-T is described in ClinVar as Benign. ClinVar VariationId is 791974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0106 (1618/152230) while in subpopulation AFR AF = 0.0374 (1555/41534). AF 95% confidence interval is 0.0359. There are 31 homozygotes in GnomAd4. There are 747 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 31 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024936.3. 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
	ZCCHC4	NM_024936.3	MANE Select	c.89C>T	p.Pro30Leu	missense	Exon 1 of 13	NP_079212.2
	ZCCHC4	NM_001318148.2		c.89C>T	p.Pro30Leu	missense	Exon 1 of 9	NP_001305077.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZCCHC4	ENST00000302874.9	TSL:1 MANE Select	c.89C>T	p.Pro30Leu	missense	Exon 1 of 13	ENSP00000303468.4	Q9H5U6-1
	ZCCHC4	ENST00000505451.5	TSL:1	n.114C>T		non_coding_transcript_exon	Exon 1 of 9
	ZCCHC4	ENST00000507760.5	TSL:1	n.89C>T		non_coding_transcript_exon	Exon 1 of 9	ENSP00000422115.1	Q9H5U6-2

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1615 AN: 152112 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.0375

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00268 AC: 669 AN: 249262 AF XY: 0.00191

Gnomad AFR exome AF: 0.0391

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.000825

GnomAD4 exome AF: 0.00106 AC: 1542 AN: 1460676 Hom.: 28 Cov.: 31 AF XY: 0.000881 AC XY: 640 AN XY: 726622

African (AFR) AF: 0.0392 AC: 1312 AN: 33434

American (AMR) AF: 0.00157 AC: 70 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86196

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53240

Middle Eastern (MID) AF: 0.000807 AC: 4 AN: 4954

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1111994

Other (OTH) AF: 0.00211 AC: 127 AN: 60304

GnomAD4 genome AF: 0.0106 AC: 1618 AN: 152230 Hom.: 31 Cov.: 32 AF XY: 0.0100 AC XY: 747 AN XY: 74424

African (AFR) AF: 0.0374 AC: 1555 AN: 41534

American (AMR) AF: 0.00301 AC: 46 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68018

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00384 Hom.: 26

Bravo AF: 0.0117

ESP6500AA AF: 0.0339 AC: 141

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00349 AC: 422

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0049	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.00066	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.15
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.054
Sift	Benign	0.18	T
Sift4G	Benign	0.31	T
Polyphen		0.0	B
Vest4		0.29
MVP		0.055
MPC		0.084
ClinPred		0.0069	T
GERP RS		1.9
PromoterAI		0.045	Neutral
Varity_R		0.14
gMVP		0.12
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs61743521; hg19: chr4-25314520;