rs41276027

Variant names:

• chr7-37894545-A-T
• rs41276027
• NM_016616.5:c.1479A>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 11 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 -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 VariationId is 164805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
NME8	NM_016616.5	c.1479A>T	p.Ile493Ile	synonymous_variant	Exon 16 of 18	ENST00000199447.9	NP_057700.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NME8	ENST00000199447.9	c.1479A>T	p.Ile493Ile	synonymous_variant	Exon 16 of 18	1	NM_016616.5	ENSP00000199447.4
NME8	ENST00000440017.5	c.1479A>T	p.Ile493Ile	synonymous_variant	Exon 15 of 16	1		ENSP00000397063.1
ENSG00000290149	ENST00000476620.1	c.-38+37200A>T		intron_variant	Intron 2 of 3	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

GnomAD2 exomes AF: 0.273 AC: 68343 AN: 250598 AF XY: 0.273

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 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

African (AFR) AF: 0.0524 AC: 1750 AN: 33394

American (AMR) AF: 0.242 AC: 10816 AN: 44604

Ashkenazi Jewish (ASJ) AF: 0.300 AC: 7809 AN: 26032

East Asian (EAS) AF: 0.157 AC: 6231 AN: 39602

South Asian (SAS) AF: 0.167 AC: 14386 AN: 86120

European-Finnish (FIN) AF: 0.333 AC: 17798 AN: 53376

Middle Eastern (MID) AF: 0.261 AC: 1497 AN: 5728

European-Non Finnish (NFE) AF: 0.359 AC: 397308 AN: 1105410

Other (OTH) AF: 0.312 AC: 18747 AN: 60104

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

African (AFR) AF: 0.0674 AC: 2800 AN: 41544

American (AMR) AF: 0.247 AC: 3773 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.306 AC: 1061 AN: 3470

East Asian (EAS) AF: 0.137 AC: 706 AN: 5166

South Asian (SAS) AF: 0.162 AC: 780 AN: 4818

European-Finnish (FIN) AF: 0.322 AC: 3396 AN: 10542

Middle Eastern (MID) AF: 0.260 AC: 76 AN: 292

European-Non Finnish (NFE) AF: 0.361 AC: 24495 AN: 67888

Other (OTH) AF: 0.272 AC: 575 AN: 2112

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

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary ciliary dyskinesia Benign:1

Dec 10, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.41
DANN	Benign	0.50
PhyloP100		-0.34
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs41276027; hg19: chr7-37934147; COSMIC: COSV52250933; COSMIC: COSV52250933;