rs117149381

Positions:

• chr7-37862001-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000199447.9(NME8):​c.271-27C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0209 in 1,407,586 control chromosomes in the GnomAD database, including 392 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (37 hom., cov: 32)
  • Exomes 𝑓: 0.021 (355 hom.)
• Consequence: NME8 ENST00000199447.9 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:4 O:1
• Conservation: PhyloP100: 0.124

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 7-37862001-C-T is Benign according to our data. Variant chr7-37862001-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0169 (2570/152262) while in subpopulation NFE AF= 0.027 (1836/68018). AF 95% confidence interval is 0.026. There are 37 homozygotes in gnomad4. There are 1192 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 37 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NME8	NM_016616.5	c.271-27C>T		intron_variant		ENST00000199447.9	NP_057700.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NME8	ENST00000199447.9	c.271-27C>T		intron_variant		1	NM_016616.5	ENSP00000199447	P1

Frequencies

GnomAD3 genomes AF: 0.0169 AC: 2570 AN: 152144 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.00355

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.0182

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00498

Gnomad FIN AF: 0.0278

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0270

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.0179 AC: 4480 AN: 250674 Hom.: 62 AF XY: 0.0180 AC XY: 2443 AN XY: 135494

Gnomad AFR exome AF: 0.00327

Gnomad AMR exome AF: 0.00866

Gnomad ASJ exome AF: 0.0174

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00519

Gnomad FIN exome AF: 0.0323

Gnomad NFE exome AF: 0.0262

Gnomad OTH exome AF: 0.0216

GnomAD4 exome AF: 0.0214 AC: 26846 AN: 1255324 Hom.: 355 Cov.: 18 AF XY: 0.0212 AC XY: 13471 AN XY: 635390

Gnomad4 AFR exome AF: 0.00429

Gnomad4 AMR exome AF: 0.00963

Gnomad4 ASJ exome AF: 0.0171

Gnomad4 EAS exome AF: 0.0000516

Gnomad4 SAS exome AF: 0.00542

Gnomad4 FIN exome AF: 0.0373

Gnomad4 NFE exome AF: 0.0242

Gnomad4 OTH exome AF: 0.0186

GnomAD4 genome AF: 0.0169 AC: 2570 AN: 152262 Hom.: 37 Cov.: 32 AF XY: 0.0160 AC XY: 1192 AN XY: 74432

Gnomad4 AFR AF: 0.00354

Gnomad4 AMR AF: 0.0109

Gnomad4 ASJ AF: 0.0182

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00498

Gnomad4 FIN AF: 0.0278

Gnomad4 NFE AF: 0.0270

Gnomad4 OTH AF: 0.0152

Alfa AF: 0.0261 Hom.: 16

Bravo AF: 0.0148

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia 6 Pathogenic:1 Benign:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 27, 2007	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 17, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 23, 2019

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.78
DANN	Benign	0.65

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: rs117149381; hg19: chr7-37901603;