4-88697656-C-G

Variant names:

• chr4-88697656-C-G
• rs546717344
• NM_153757.4:c.99G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_153757.4(NAP1L5):​c.99G>C​(p.Gln33His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: NAP1L5 NM_153757.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.973

Genes affected

NAP1L5 (HGNC:19968): (nucleosome assembly protein 1 like 5) This gene encodes a protein that shares sequence similarity to nucleosome assembly factors, but may be localized to the cytoplasm rather than the nucleus. Expression of this gene is downregulated in hepatocellular carcinomas. This gene is located within a differentially methylated region (DMR) and is imprinted and paternally expressed. There is a related pseudogene on chromosome 4. [provided by RefSeq, Nov 2015]

HERC3 (HGNC:4876): (HECT and RLD domain containing E3 ubiquitin protein ligase 3) This gene encodes a member the HERC ubiquitin ligase family. The encoded protein is located in the cytosol and binds ubiquitin via a HECT domain. Mutations in this gene have been associated with colorectal and gastric carcinomas. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Oct 2012]

HERC3 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.102538615).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAP1L5	NM_153757.4	c.99G>C	p.Gln33His	missense_variant	Exon 1 of 1	ENST00000323061.7	NP_715638.1
HERC3	NM_014606.3	c.2658-6442C>G		intron_variant	Intron 23 of 25	ENST00000402738.6	NP_055421.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAP1L5	ENST00000323061.7	c.99G>C	p.Gln33His	missense_variant	Exon 1 of 1	6	NM_153757.4	ENSP00000320488.5
HERC3	ENST00000402738.6	c.2658-6442C>G		intron_variant	Intron 23 of 25	1	NM_014606.3	ENSP00000385684.1
HERC3	ENST00000264345.7	c.2658-6442C>G		intron_variant	Intron 21 of 23	1
HERC3	ENST00000512194.2	c.2634-6442C>G		intron_variant	Intron 23 of 25	5		ENSP00000421021.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248726 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135062

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000552

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461152 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726916

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.045
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.13	T
Polyphen		0.84	P
Vest4		0.13
MutPred		0.16		Gain of catalytic residue at G34 (P = 0.1066);
MVP		0.10
MPC		0.25
ClinPred		0.11	T
GERP RS		0.79
Varity_R		0.21
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs546717344; hg19: chr4-89618807;