rs3213975

Positions:

• chr7-37896928-T-C

Variant summary

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

The NM_016616.5(NME8):​c.1603T>C​(p.Leu535=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 1,613,196 control chromosomes in the GnomAD database, including 44,033 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (3886 hom., cov: 31)
  • Exomes 𝑓: 0.23 (40147 hom.)
• Consequence: NME8 NM_016616.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.314

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=-0.84).
• BP6: Variant 7-37896928-T-C is Benign according to our data. Variant chr7-37896928-T-C is described in ClinVar as [Benign]. Clinvar id is 164806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.314 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.232 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NME8	NM_016616.5	c.1603T>C	p.Leu535=	synonymous_variant	17/18	ENST00000199447.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NME8	ENST00000199447.9	c.1603T>C	p.Leu535=	synonymous_variant	17/18	1	NM_016616.5	P1
NME8	ENST00000440017.5	c.1603T>C	p.Leu535=	synonymous_variant	16/16	1		P1
NME8	ENST00000476435.1	n.112T>C		non_coding_transcript_exon_variant	1/2	1

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34381 AN: 151760 Hom.: 3883 Cov.: 31

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.227

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.222

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.244

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.235

Gnomad OTH AF: 0.220

GnomAD3 exomes AF: 0.242 AC: 60776 AN: 251196 Hom.: 7563 AF XY: 0.244 AC XY: 33121 AN XY: 135744

Gnomad AFR exome AF: 0.202

Gnomad AMR exome AF: 0.274

Gnomad ASJ exome AF: 0.267

Gnomad EAS exome AF: 0.231

Gnomad SAS exome AF: 0.229

Gnomad FIN exome AF: 0.250

Gnomad NFE exome AF: 0.240

Gnomad OTH exome AF: 0.238

GnomAD4 exome AF: 0.233 AC: 340358 AN: 1461318 Hom.: 40147 Cov.: 35 AF XY: 0.233 AC XY: 169736 AN XY: 726982

Gnomad4 AFR exome AF: 0.205

Gnomad4 AMR exome AF: 0.266

Gnomad4 ASJ exome AF: 0.262

Gnomad4 EAS exome AF: 0.224

Gnomad4 SAS exome AF: 0.228

Gnomad4 FIN exome AF: 0.242

Gnomad4 NFE exome AF: 0.232

Gnomad4 OTH exome AF: 0.231

GnomAD4 genome AF: 0.227 AC: 34408 AN: 151878 Hom.: 3886 Cov.: 31 AF XY: 0.227 AC XY: 16847 AN XY: 74200

Gnomad4 AFR AF: 0.206

Gnomad4 AMR AF: 0.227

Gnomad4 ASJ AF: 0.266

Gnomad4 EAS AF: 0.221

Gnomad4 SAS AF: 0.226

Gnomad4 FIN AF: 0.244

Gnomad4 NFE AF: 0.235

Gnomad4 OTH AF: 0.220

Alfa AF: 0.238 Hom.: 5868

Bravo AF: 0.229

Asia WGS AF: 0.229 AC: 796 AN: 3478

EpiCase AF: 0.239

EpiControl AF: 0.245

ClinVar

Significance: Benign

Submissions summary: Benign:5

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	Leu535Leu in exon 17 of TXNDC3: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 24.2% (2077/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs3213975). -

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 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

Nov 12, 2018

- -

Primary ciliary dyskinesia 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.45
DANN	Benign	0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs3213975; hg19: chr7-37936530; COSMIC: COSV52247394;