rs2598044

Positions:

• chr7-37850714-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000199447.9(NME8):​c.177C>T​(p.Asp59=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 1,605,020 control chromosomes in the GnomAD database, including 49,984 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6014 hom., cov: 33)
  • Exomes 𝑓: 0.24 (43970 hom.)
• Consequence: NME8 ENST00000199447.9 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.953

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 7-37850714-C-T is Benign according to our data. Variant chr7-37850714-C-T is described in ClinVar as [Benign]. Clinvar id is 164799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.953 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.361 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NME8	NM_016616.5	c.177C>T	p.Asp59=	synonymous_variant	5/18	ENST00000199447.9	NP_057700.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NME8	ENST00000199447.9	c.177C>T	p.Asp59=	synonymous_variant	5/18	1	NM_016616.5	ENSP00000199447	P1

Frequencies

GnomAD3 genomes AF: 0.275 AC: 41818 AN: 151936 Hom.: 6003 Cov.: 33

Gnomad AFR AF: 0.365

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.280

Gnomad EAS AF: 0.180

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.245

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.249

Gnomad OTH AF: 0.257

GnomAD3 exomes AF: 0.229 AC: 57476 AN: 250792 Hom.: 7102 AF XY: 0.224 AC XY: 30324 AN XY: 135520

Gnomad AFR exome AF: 0.374

Gnomad AMR exome AF: 0.203

Gnomad ASJ exome AF: 0.282

Gnomad EAS exome AF: 0.185

Gnomad SAS exome AF: 0.136

Gnomad FIN exome AF: 0.236

Gnomad NFE exome AF: 0.242

Gnomad OTH exome AF: 0.236

GnomAD4 exome AF: 0.241 AC: 349803 AN: 1452966 Hom.: 43970 Cov.: 31 AF XY: 0.238 AC XY: 172214 AN XY: 723382

Gnomad4 AFR exome AF: 0.370

Gnomad4 AMR exome AF: 0.207

Gnomad4 ASJ exome AF: 0.281

Gnomad4 EAS exome AF: 0.183

Gnomad4 SAS exome AF: 0.138

Gnomad4 FIN exome AF: 0.235

Gnomad4 NFE exome AF: 0.248

Gnomad4 OTH exome AF: 0.242

GnomAD4 genome AF: 0.275 AC: 41860 AN: 152054 Hom.: 6014 Cov.: 33 AF XY: 0.272 AC XY: 20220 AN XY: 74332

Gnomad4 AFR AF: 0.366

Gnomad4 AMR AF: 0.250

Gnomad4 ASJ AF: 0.280

Gnomad4 EAS AF: 0.180

Gnomad4 SAS AF: 0.136

Gnomad4 FIN AF: 0.245

Gnomad4 NFE AF: 0.250

Gnomad4 OTH AF: 0.256

Alfa AF: 0.254 Hom.: 3742

Bravo AF: 0.277

Asia WGS AF: 0.164 AC: 571 AN: 3478

EpiCase AF: 0.246

EpiControl AF: 0.246

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Asp59Asp in exon 5 of TXNDC3: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 36.8% (1622/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2598044). -

Primary ciliary dyskinesia 6 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 10, 2014

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

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	1.0
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2598044; hg19: chr7-37890316; COSMIC: COSV52250626;