4-88697686-T-C

Variant names:

• chr4-88697686-T-C
• rs710834
• NM_153757.4:c.69A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_153757.4(NAP1L5):​c.69A>G​(p.Ala23Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.402 in 1,611,472 control chromosomes in the GnomAD database, including 137,356 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.47 (18094 hom., cov: 32)
  • Exomes 𝑓: 0.40 (119262 hom.)
• Consequence: NAP1L5 NM_153757.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.927

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

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP7: Synonymous conserved (PhyloP=-0.927 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.649 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAP1L5	NM_153757.4	c.69A>G	p.Ala23Ala	synonymous_variant	Exon 1 of 1	ENST00000323061.7	NP_715638.1
HERC3	NM_014606.3	c.2658-6412T>C		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.69A>G	p.Ala23Ala	synonymous_variant	Exon 1 of 1	6	NM_153757.4	ENSP00000320488.5
HERC3	ENST00000402738.6	c.2658-6412T>C		intron_variant	Intron 23 of 25	1	NM_014606.3	ENSP00000385684.1
HERC3	ENST00000264345.7	c.2658-6412T>C		intron_variant	Intron 21 of 23	1
HERC3	ENST00000512194.2	c.2634-6412T>C		intron_variant	Intron 23 of 25	5		ENSP00000421021.2

Frequencies

GnomAD3 genomes AF: 0.470 AC: 71414 AN: 151790 Hom.: 18054 Cov.: 32

Gnomad AFR AF: 0.656

Gnomad AMI AF: 0.410

Gnomad AMR AF: 0.437

Gnomad ASJ AF: 0.290

Gnomad EAS AF: 0.561

Gnomad SAS AF: 0.598

Gnomad FIN AF: 0.451

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.364

Gnomad OTH AF: 0.435

GnomAD2 exomes AF: 0.431 AC: 105180 AN: 243920 AF XY: 0.432

Gnomad AFR exome AF: 0.674

Gnomad AMR exome AF: 0.387

Gnomad ASJ exome AF: 0.304

Gnomad EAS exome AF: 0.549

Gnomad FIN exome AF: 0.450

Gnomad NFE exome AF: 0.361

Gnomad OTH exome AF: 0.395

GnomAD4 exome AF: 0.395 AC: 577092 AN: 1459564 Hom.: 119262 Cov.: 61 AF XY: 0.399 AC XY: 289502 AN XY: 726138

Gnomad4 AFR exome AF: 0.674 AC: 22541 AN: 33462

Gnomad4 AMR exome AF: 0.393 AC: 17523 AN: 44630

Gnomad4 ASJ exome AF: 0.299 AC: 7806 AN: 26092

Gnomad4 EAS exome AF: 0.594 AC: 23550 AN: 39672

Gnomad4 SAS exome AF: 0.574 AC: 49474 AN: 86210

Gnomad4 FIN exome AF: 0.444 AC: 23092 AN: 51956

Gnomad4 NFE exome AF: 0.365 AC: 405560 AN: 1111494

Gnomad4 Remaining exome AF: 0.418 AC: 25227 AN: 60306

GnomAD4 genome AF: 0.471 AC: 71504 AN: 151908 Hom.: 18094 Cov.: 32 AF XY: 0.478 AC XY: 35506 AN XY: 74254

Gnomad4 AFR AF: 0.656 AC: 0.6556 AN: 0.6556

Gnomad4 AMR AF: 0.437 AC: 0.43669 AN: 0.43669

Gnomad4 ASJ AF: 0.290 AC: 0.290295 AN: 0.290295

Gnomad4 EAS AF: 0.562 AC: 0.56182 AN: 0.56182

Gnomad4 SAS AF: 0.596 AC: 0.596178 AN: 0.596178

Gnomad4 FIN AF: 0.451 AC: 0.451071 AN: 0.451071

Gnomad4 NFE AF: 0.364 AC: 0.363766 AN: 0.363766

Gnomad4 OTH AF: 0.442 AC: 0.441651 AN: 0.441651

Alfa AF: 0.377 Hom.: 10053

Bravo AF: 0.472

Asia WGS AF: 0.639 AC: 2221 AN: 3478

EpiCase AF: 0.358

EpiControl AF: 0.359

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	10
DANN	Benign	0.83
Mutation Taster		=100/0	polymorphism (auto)

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: rs710834; hg19: chr4-89618837; COSMIC: COSV52019390;