chr5-71011290-G-A

Position:

• chr5-71011290-G-A

Variant summary

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

The NM_004536.3(NAIP):​c.653C>T​(p.Ala218Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000428 in 1,447,064 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000043 (1 hom.)
• Consequence: NAIP NM_004536.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.67

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NAIP	NM_004536.3	c.653C>T	p.Ala218Val	missense_variant	5/17	ENST00000517649.6	NP_004527.2
NAIP	NM_001346870.2	c.653C>T	p.Ala218Val	missense_variant	5/17		NP_001333799.1
NAIP	NM_022892.2	c.183-7433C>T		intron_variant			NP_075043.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NAIP	ENST00000517649.6	c.653C>T	p.Ala218Val	missense_variant	5/17	1	NM_004536.3	ENSP00000428657.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000428 AC: 62 AN: 1447064 Hom.: 1 Cov.: 30 AF XY: 0.0000389 AC XY: 28 AN XY: 719902

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000562

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2024

The c.653C>T (p.A218V) alteration is located in exon 5 (coding exon 2) of the NAIP gene. This alteration results from a C to T substitution at nucleotide position 653, causing the alanine (A) at amino acid position 218 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;T;.
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.52	D
LIST_S2	Uncertain	0.94	D;.;D
M_CAP	Benign	0.084	D
MetaRNN	Uncertain	0.55	D;D;D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Uncertain	2.0	M;M;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Uncertain	0.42
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.45
MutPred		0.49		Gain of methylation at K215 (P = 0.098);Gain of methylation at K215 (P = 0.098);Gain of methylation at K215 (P = 0.098);
MVP		0.83
MPC		0.67
ClinPred		0.90	D
GERP RS		2.0
Varity_R		0.24
gMVP		0.055

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: rs1580932678; hg19: chr5-70307117;