5-71012727-C-A

Position:

• chr5-71012727-C-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004536.3(NAIP):​c.189G>T​(p.Arg63Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00514 in 1,611,724 control chromosomes in the GnomAD database, including 296 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (22 hom., cov: 33)
  • Exomes 𝑓: 0.0053 (274 hom.)
• Consequence: NAIP NM_004536.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.609

Genes affected

NAIP (HGNC:7634): (NLR family apoptosis inhibitory protein) This gene is part of a 500 kb inverted duplication on chromosome 5q13. This duplicated region contains at least four genes and repetitive elements which make it prone to rearrangements and deletions. The repetitiveness and complexity of the sequence have also caused difficulty in determining the organization of this genomic region. This copy of the gene is full length; additional copies with truncations and internal deletions are also present in this region of chromosome 5q13. It is thought that this gene is a modifier of spinal muscular atrophy caused by mutations in a neighboring gene, SMN1. The protein encoded by this gene contains regions of homology to two baculovirus inhibitor of apoptosis proteins, and it is able to suppress apoptosis induced by various signals. Alternative splicing and the use of alternative promoters results in multiple transcript variants. [provided by RefSeq, Nov 2016]

NAIP (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05929655).
• BP6: Variant 5-71012727-C-A is Benign according to our data. Variant chr5-71012727-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 710844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NAIP	NM_004536.3	c.189G>T	p.Arg63Ser	missense_variant	4/17	ENST00000517649.6	NP_004527.2
NAIP	NM_001346870.2	c.189G>T	p.Arg63Ser	missense_variant	4/17		NP_001333799.1
NAIP	NM_022892.2	c.182+7932G>T		intron_variant			NP_075043.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NAIP	ENST00000517649.6	c.189G>T	p.Arg63Ser	missense_variant	4/17	1	NM_004536.3	ENSP00000428657.2

Frequencies

GnomAD3 genomes AF: 0.00327 AC: 495 AN: 151508 Hom.: 22 Cov.: 33

Gnomad AFR AF: 0.00119

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000417

Gnomad FIN AF: 0.00362

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00541

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00311 AC: 780 AN: 251092 Hom.: 31 AF XY: 0.00324 AC XY: 439 AN XY: 135702

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000850

Gnomad FIN exome AF: 0.00444

Gnomad NFE exome AF: 0.00508

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00533 AC: 7785 AN: 1460098 Hom.: 274 Cov.: 35 AF XY: 0.00517 AC XY: 3758 AN XY: 726380

Gnomad4 AFR exome AF: 0.000897

Gnomad4 AMR exome AF: 0.00163

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000673

Gnomad4 FIN exome AF: 0.00444

Gnomad4 NFE exome AF: 0.00644

Gnomad4 OTH exome AF: 0.00378

GnomAD4 genome AF: 0.00326 AC: 495 AN: 151626 Hom.: 22 Cov.: 33 AF XY: 0.00314 AC XY: 233 AN XY: 74116

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.00125

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000417

Gnomad4 FIN AF: 0.00362

Gnomad4 NFE AF: 0.00541

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00460 Hom.: 26

Bravo AF: 0.00283

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00535 AC: 46

ExAC AF: 0.00299 AC: 363

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 08, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D;D;.
Eigen	Benign	0.020
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.85	T;.;T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.059	T;T;T
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	4.2	H;H;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.73
MutPred		0.82		Gain of ubiquitination at K65 (P = 0.0398);Gain of ubiquitination at K65 (P = 0.0398);Gain of ubiquitination at K65 (P = 0.0398);
MVP		0.94
MPC		0.72
ClinPred		0.086	T
GERP RS		2.2
Varity_R		0.42
gMVP		0.88

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

Publications

LitVar

Other links and lift over

dbSNP: rs115486998; hg19: chr5-70308554;