NM_017612.5:c.2073G>A

Variant names:

• chr12-122473548-C-T
• rs78310827
• NM_017612.5:c.2073G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_017612.5(ZCCHC8):​c.2073G>A​(p.Leu691Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00538 in 1,613,946 control chromosomes in the GnomAD database, including 275 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (140 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (135 hom.)
• Consequence: ZCCHC8 NM_017612.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.28
• Publications: 2 publications found

Genes affected

ZCCHC8 (HGNC:25265): (zinc finger CCHC-type containing 8) This gene encodes a scaffold protein which serves as an assessory factor to the nuclear RNA exosome complex. The encoded protein forms a trimeric human nuclear exosome targeting (NEXT) complex, together with hMTR4 and the RNA-binding factor RBM7 which promotes the exosomal degradation of non-coding promoter-upstream transcripts, enhancer RNAs and 3'-extended products of histone- and small nuclear RNA transcription. This complex is also thought to recruit the exosome to degrade intronic RNAs via its interaction with both the exosome and the spliceosome. It contains both an N-terminal zinc-knuckle domain and a C-terminal proline-rich domain. [provided by RefSeq, Apr 2017]

ZCCHC8 Gene-Disease associations (from GenCC):

• pulmonary fibrosis and/or bone marrow failure, telomere-related, 5

  Inheritance: Unknown, AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• intellectual disability

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 12-122473548-C-T is Benign according to our data. Variant chr12-122473548-C-T is described in ClinVar as Benign. ClinVar VariationId is 784476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.28 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0822 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017612.5. 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
	ZCCHC8	NM_017612.5	MANE Select	c.2073G>A	p.Leu691Leu	synonymous	Exon 14 of 14	NP_060082.2
	ZCCHC8	NM_001350935.2		c.1842G>A	p.Leu614Leu	synonymous	Exon 11 of 11	NP_001337864.1
	ZCCHC8	NM_001350936.2		c.1776G>A	p.Leu592Leu	synonymous	Exon 13 of 13	NP_001337865.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZCCHC8	ENST00000633063.3	TSL:1 MANE Select	c.2073G>A	p.Leu691Leu	synonymous	Exon 14 of 14	ENSP00000488055.1	Q6NZY4-1
	ZCCHC8	ENST00000536306.5	TSL:1	c.1359G>A	p.Leu453Leu	synonymous	Exon 12 of 12	ENSP00000441423.1	Q6NZY4-2
	ZCCHC8	ENST00000543897.5	TSL:1	c.1359G>A	p.Leu453Leu	synonymous	Exon 12 of 12	ENSP00000438993.1	Q6NZY4-2

Frequencies

GnomAD3 genomes AF: 0.0253 AC: 3849 AN: 152132 Hom.: 141 Cov.: 32

Gnomad AFR AF: 0.0846

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0108

Gnomad ASJ AF: 0.0280

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.00788 AC: 1965 AN: 249216 AF XY: 0.00638

Gnomad AFR exome AF: 0.0900

Gnomad AMR exome AF: 0.00582

Gnomad ASJ exome AF: 0.0251

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000752

Gnomad OTH exome AF: 0.00529

GnomAD4 exome AF: 0.00330 AC: 4824 AN: 1461696 Hom.: 135 Cov.: 31 AF XY: 0.00291 AC XY: 2119 AN XY: 727126

African (AFR) AF: 0.0888 AC: 2973 AN: 33478

American (AMR) AF: 0.00619 AC: 277 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0280 AC: 733 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00416 AC: 24 AN: 5766

European-Non Finnish (NFE) AF: 0.000314 AC: 349 AN: 1111866

Other (OTH) AF: 0.00760 AC: 459 AN: 60374

GnomAD4 genome AF: 0.0253 AC: 3856 AN: 152250 Hom.: 140 Cov.: 32 AF XY: 0.0248 AC XY: 1844 AN XY: 74460

African (AFR) AF: 0.0845 AC: 3510 AN: 41532

American (AMR) AF: 0.0108 AC: 165 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0280 AC: 97 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000735 AC: 50 AN: 68022

Other (OTH) AF: 0.0132 AC: 28 AN: 2114

Alfa AF: 0.00827 Hom.: 93

Bravo AF: 0.0290

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00119

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	-0.38
CADD	Benign	11
DANN	Benign	0.72
PhyloP100		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs78310827; hg19: chr12-122958095;