chr7-37894545-A-T

Position:

• chr7-37894545-A-T

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.1479A>T​(p.Ile493Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.32 in 1,606,362 control chromosomes in the GnomAD database, including 88,552 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (6052 hom., cov: 32)
  • Exomes 𝑓: 0.33 (82500 hom.)
• Consequence: NME8 NM_016616.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.337

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]

ENSG00000290149 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 7-37894545-A-T is Benign according to our data. Variant chr7-37894545-A-T is described in ClinVar as [Benign]. Clinvar id is 164805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-37894545-A-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.337 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NME8	NM_016616.5	c.1479A>T	p.Ile493Ile	synonymous_variant	16/18	ENST00000199447.9	NP_057700.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NME8	ENST00000199447.9	c.1479A>T	p.Ile493Ile	synonymous_variant	16/18	1	NM_016616.5	ENSP00000199447.4
NME8	ENST00000440017.5	c.1479A>T	p.Ile493Ile	synonymous_variant	15/16	1		ENSP00000397063.1
ENSG00000290149	ENST00000476620.1	c.-38+37200A>T		intron_variant		4		ENSP00000425858.1

Frequencies

GnomAD3 genomes AF: 0.251 AC: 38047 AN: 151874 Hom.: 6051 Cov.: 32

Gnomad AFR AF: 0.0676

Gnomad AMI AF: 0.416

Gnomad AMR AF: 0.247

Gnomad ASJ AF: 0.306

Gnomad EAS AF: 0.137

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.322

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.361

Gnomad OTH AF: 0.276

GnomAD3 exomes AF: 0.273 AC: 68343 AN: 250598 Hom.: 10693 AF XY: 0.273 AC XY: 37013 AN XY: 135518

Gnomad AFR exome AF: 0.0591

Gnomad AMR exome AF: 0.237

Gnomad ASJ exome AF: 0.297

Gnomad EAS exome AF: 0.128

Gnomad SAS exome AF: 0.163

Gnomad FIN exome AF: 0.327

Gnomad NFE exome AF: 0.353

Gnomad OTH exome AF: 0.305

GnomAD4 exome AF: 0.328 AC: 476342 AN: 1454370 Hom.: 82500 Cov.: 34 AF XY: 0.324 AC XY: 234386 AN XY: 723898

Gnomad4 AFR exome AF: 0.0524

Gnomad4 AMR exome AF: 0.242

Gnomad4 ASJ exome AF: 0.300

Gnomad4 EAS exome AF: 0.157

Gnomad4 SAS exome AF: 0.167

Gnomad4 FIN exome AF: 0.333

Gnomad4 NFE exome AF: 0.359

Gnomad4 OTH exome AF: 0.312

GnomAD4 genome AF: 0.250 AC: 38037 AN: 151992 Hom.: 6052 Cov.: 32 AF XY: 0.246 AC XY: 18266 AN XY: 74284

Gnomad4 AFR AF: 0.0674

Gnomad4 AMR AF: 0.247

Gnomad4 ASJ AF: 0.306

Gnomad4 EAS AF: 0.137

Gnomad4 SAS AF: 0.162

Gnomad4 FIN AF: 0.322

Gnomad4 NFE AF: 0.361

Gnomad4 OTH AF: 0.272

Alfa AF: 0.328 Hom.: 2807

Bravo AF: 0.240

Asia WGS AF: 0.152 AC: 528 AN: 3474

EpiCase AF: 0.350

EpiControl AF: 0.343

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Ile493Ile in exon 16 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 0.5% (47/8598) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs41276027). -
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

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

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.41
DANN	Benign	0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs41276027; hg19: chr7-37934147; COSMIC: COSV52250933; COSMIC: COSV52250933;