5-71012424-C-T

Variant names:

• chr5-71012424-C-T
• rs28409706
• NM_004536.3:c.492G>A

Variant summary

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

The NM_004536.3(NAIP):​c.492G>A​(p.Ala164Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.778 in 1,610,560 control chromosomes in the GnomAD database, including 497,378 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. Synonymous variant affecting the same amino acid position (i.e. A164A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.83 (52656 hom., cov: 33)
  • Exomes 𝑓: 0.77 (444722 hom.)
• Consequence: NAIP NM_004536.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.19
• Publications: 27 publications found

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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP7: Synonymous conserved (PhyloP=-1.19 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.941 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004536.3. 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
	NAIP	NM_004536.3	MANE Select	c.492G>A	p.Ala164Ala	synonymous	Exon 4 of 17	NP_004527.2	Q13075-1
	NAIP	NM_001346870.2		c.492G>A	p.Ala164Ala	synonymous	Exon 4 of 17	NP_001333799.1	Q13075-1
	NAIP	NM_022892.2		c.182+8235G>A		intron	N/A	NP_075043.1	Q13075-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAIP	ENST00000517649.6	TSL:1 MANE Select	c.492G>A	p.Ala164Ala	synonymous	Exon 4 of 17	ENSP00000428657.2	Q13075-1
	NAIP	ENST00000194097.8	TSL:1	c.492G>A	p.Ala164Ala	synonymous	Exon 2 of 15	ENSP00000443944.1	Q13075-1
	NAIP	ENST00000508426.6	TSL:1	c.492G>A	p.Ala164Ala	synonymous	Exon 2 of 14	ENSP00000429545.1	E7EQW0

Frequencies

GnomAD3 genomes AF: 0.826 AC: 124773 AN: 151046 Hom.: 52589 Cov.: 33

Gnomad AFR AF: 0.949

Gnomad AMI AF: 0.740

Gnomad AMR AF: 0.835

Gnomad ASJ AF: 0.616

Gnomad EAS AF: 0.900

Gnomad SAS AF: 0.820

Gnomad FIN AF: 0.827

Gnomad MID AF: 0.617

Gnomad NFE AF: 0.758

Gnomad OTH AF: 0.779

GnomAD2 exomes AF: 0.801 AC: 201116 AN: 251000 AF XY: 0.794

Gnomad AFR exome AF: 0.953

Gnomad AMR exome AF: 0.873

Gnomad ASJ exome AF: 0.615

Gnomad EAS exome AF: 0.905

Gnomad FIN exome AF: 0.827

Gnomad NFE exome AF: 0.754

Gnomad OTH exome AF: 0.765

GnomAD4 exome AF: 0.773 AC: 1127770 AN: 1459396 Hom.: 444722 Cov.: 68 AF XY: 0.772 AC XY: 560410 AN XY: 726062

African (AFR) AF: 0.953 AC: 31883 AN: 33466

American (AMR) AF: 0.867 AC: 38746 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.620 AC: 16188 AN: 26120

East Asian (EAS) AF: 0.878 AC: 34828 AN: 39680

South Asian (SAS) AF: 0.802 AC: 69121 AN: 86162

European-Finnish (FIN) AF: 0.826 AC: 44029 AN: 53284

Middle Eastern (MID) AF: 0.654 AC: 3764 AN: 5758

European-Non Finnish (NFE) AF: 0.759 AC: 842668 AN: 1109948

Other (OTH) AF: 0.772 AC: 46543 AN: 60288

GnomAD4 genome AF: 0.826 AC: 124903 AN: 151164 Hom.: 52656 Cov.: 33 AF XY: 0.828 AC XY: 61156 AN XY: 73844

African (AFR) AF: 0.949 AC: 39165 AN: 41260

American (AMR) AF: 0.835 AC: 12660 AN: 15160

Ashkenazi Jewish (ASJ) AF: 0.616 AC: 2134 AN: 3462

East Asian (EAS) AF: 0.900 AC: 4641 AN: 5154

South Asian (SAS) AF: 0.819 AC: 3915 AN: 4782

European-Finnish (FIN) AF: 0.827 AC: 8612 AN: 10418

Middle Eastern (MID) AF: 0.616 AC: 181 AN: 294

European-Non Finnish (NFE) AF: 0.758 AC: 51282 AN: 67624

Other (OTH) AF: 0.781 AC: 1640 AN: 2100

Alfa AF: 0.778 Hom.: 30136

Bravo AF: 0.832

Asia WGS AF: 0.893 AC: 3108 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	3.1
DANN	Benign	0.37
PhyloP100		-1.2
Mutation Taster		=99/1	polymorphism (auto)

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: rs28409706; hg19: chr5-70308251; COSMIC: COSV52000849; COSMIC: COSV52000849;