NM_016616.5:c.1247+25A>G

Variant names:

• chr7-37885277-A-G
• rs2242027
• NM_016616.5:c.1247+25A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016616.5(NME8):​c.1247+25A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.487 in 1,427,886 control chromosomes in the GnomAD database, including 174,169 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (17128 hom., cov: 32)
  • Exomes 𝑓: 0.49 (157041 hom.)
• Consequence: NME8 NM_016616.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.02
• Publications: 7 publications found

Genes affected

NME8 (HGNC:16473): (NME/NM23 family member 8) This gene encodes a protein with an N-terminal thioredoxin domain and three C-terminal nucleoside diphosphate kinase (NDK) domains, but the NDK domains are thought to be catalytically inactive. The sea urchin ortholog of this gene encodes a component of sperm outer dynein arms, and the protein is implicated in ciliary function. Mutations in this gene are implicated in primary ciliary dyskinesia type 6.[provided by RefSeq, Nov 2009]

NME8 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• primary ciliary dyskinesia 6

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics

ENSG00000290149 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 7-37885277-A-G is Benign according to our data. Variant chr7-37885277-A-G is described in ClinVar as Benign. ClinVar VariationId is 260754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.718 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016616.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NME8	NM_016616.5	MANE Select	c.1247+25A>G		intron	N/A	NP_057700.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NME8	ENST00000199447.9	TSL:1 MANE Select	c.1247+25A>G		intron	N/A	ENSP00000199447.4
	NME8	ENST00000440017.5	TSL:1	c.1247+25A>G		intron	N/A	ENSP00000397063.1
	ENSG00000290149	ENST00000476620.1	TSL:4	c.-38+27932A>G		intron	N/A	ENSP00000425858.1

Frequencies

GnomAD3 genomes AF: 0.469 AC: 71174 AN: 151884 Hom.: 17109 Cov.: 32

Gnomad AFR AF: 0.389

Gnomad AMI AF: 0.395

Gnomad AMR AF: 0.522

Gnomad ASJ AF: 0.350

Gnomad EAS AF: 0.737

Gnomad SAS AF: 0.618

Gnomad FIN AF: 0.537

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.471

Gnomad OTH AF: 0.455

GnomAD2 exomes AF: 0.510 AC: 123409 AN: 242034 AF XY: 0.511

Gnomad AFR exome AF: 0.381

Gnomad AMR exome AF: 0.528

Gnomad ASJ exome AF: 0.356

Gnomad EAS exome AF: 0.744

Gnomad FIN exome AF: 0.527

Gnomad NFE exome AF: 0.469

Gnomad OTH exome AF: 0.480

GnomAD4 exome AF: 0.489 AC: 623773 AN: 1275884 Hom.: 157041 Cov.: 18 AF XY: 0.492 AC XY: 316562 AN XY: 644070

African (AFR) AF: 0.385 AC: 11447 AN: 29704

American (AMR) AF: 0.525 AC: 23055 AN: 43894

Ashkenazi Jewish (ASJ) AF: 0.355 AC: 8859 AN: 24940

East Asian (EAS) AF: 0.734 AC: 28242 AN: 38468

South Asian (SAS) AF: 0.604 AC: 49458 AN: 81886

European-Finnish (FIN) AF: 0.530 AC: 28110 AN: 53062

Middle Eastern (MID) AF: 0.391 AC: 2119 AN: 5426

European-Non Finnish (NFE) AF: 0.472 AC: 445654 AN: 944212

Other (OTH) AF: 0.494 AC: 26829 AN: 54292

GnomAD4 genome AF: 0.469 AC: 71220 AN: 152002 Hom.: 17128 Cov.: 32 AF XY: 0.477 AC XY: 35440 AN XY: 74300

African (AFR) AF: 0.389 AC: 16132 AN: 41442

American (AMR) AF: 0.523 AC: 7988 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.350 AC: 1213 AN: 3468

East Asian (EAS) AF: 0.737 AC: 3799 AN: 5154

South Asian (SAS) AF: 0.617 AC: 2977 AN: 4822

European-Finnish (FIN) AF: 0.537 AC: 5663 AN: 10552

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.471 AC: 32027 AN: 67978

Other (OTH) AF: 0.450 AC: 948 AN: 2106

Alfa AF: 0.377 Hom.: 2192

Bravo AF: 0.461

Asia WGS AF: 0.648 AC: 2253 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Primary ciliary dyskinesia 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.2
DANN	Benign	0.64
PhyloP100		1.0
Mutation Taster		=100/0	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: rs2242027; hg19: chr7-37924879; COSMIC: COSV52250286;