rs200424572

Variant names:

• chr4-88697561-G-A
• rs200424572
• NM_153757.4:c.194C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-88697561-G-A
• chr4-88697561-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_153757.4(NAP1L5):​c.194C>T​(p.Pro65Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P65S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NAP1L5 NM_153757.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.80
• Publications: 4 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12795576).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153757.4. 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
	NAP1L5	NM_153757.4	MANE Select	c.194C>T	p.Pro65Leu	missense	Exon 1 of 1	NP_715638.1	Q96NT1
	HERC3	NM_014606.3	MANE Select	c.2658-6537G>A		intron	N/A	NP_055421.1	Q15034-1
	HERC3	NM_001375480.1		c.2655-6537G>A		intron	N/A	NP_001362409.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAP1L5	ENST00000323061.7	TSL:6 MANE Select	c.194C>T	p.Pro65Leu	missense	Exon 1 of 1	ENSP00000320488.5	Q96NT1
	HERC3	ENST00000402738.6	TSL:1 MANE Select	c.2658-6537G>A		intron	N/A	ENSP00000385684.1	Q15034-1
	HERC3	ENST00000512194.2	TSL:5	c.2634-6537G>A		intron	N/A	ENSP00000421021.2	H0Y8G9

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151956 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461840 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727220

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151956 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74202

African (AFR) AF: 0.00 AC: 0 AN: 41346

American (AMR) AF: 0.00 AC: 0 AN: 15250

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.017	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.041
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L
PhyloP100		1.8
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	1.6	N
REVEL	Benign	0.11
Sift	Benign	0.080	T
Sift4G	Benign	0.22	T
Polyphen		1.0	D
Vest4		0.14
MutPred		0.23		Loss of glycosylation at P63 (P = 0.0103)
MVP		0.11
MPC		0.28
ClinPred		0.71	D
GERP RS		3.2
PromoterAI		-0.097	Neutral
Varity_R		0.086
gMVP		0.38
Mutation Taster		=97/3	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

dbSNP: rs200424572; hg19: chr4-89618712; COSMIC: COSV52022044;