NM_017612.5:c.1960A>G

Variant names:

• chr12-122473661-T-C
• NM_017612.5:c.1960A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017612.5(ZCCHC8):​c.1960A>G​(p.Thr654Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T654I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZCCHC8 NM_017612.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.20
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04357043).

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.1960A>G	p.Thr654Ala	missense	Exon 14 of 14	NP_060082.2
	ZCCHC8	NM_001350935.2		c.1729A>G	p.Thr577Ala	missense	Exon 11 of 11	NP_001337864.1
	ZCCHC8	NM_001350936.2		c.1663A>G	p.Thr555Ala	missense	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.1960A>G	p.Thr654Ala	missense	Exon 14 of 14	ENSP00000488055.1	Q6NZY4-1
	ZCCHC8	ENST00000536306.5	TSL:1	c.1246A>G	p.Thr416Ala	missense	Exon 12 of 12	ENSP00000441423.1	Q6NZY4-2
	ZCCHC8	ENST00000543897.5	TSL:1	c.1246A>G	p.Thr416Ala	missense	Exon 12 of 12	ENSP00000438993.1	Q6NZY4-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.017
DANN	Benign	0.64
DEOGEN2	Benign	0.0049	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		-1.2
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.027
Sift	Benign	0.84	T
Sift4G	Benign	0.85	T
Polyphen		0.0010	B
Vest4		0.015
MutPred		0.22		Gain of catalytic residue at K655 (P = 0.0067)
MVP		0.12
ClinPred		0.030	T
GERP RS		-0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.016
gMVP		0.13
Mutation Taster		=92/8	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

hg19: chr12-122958208;