rs56128139

Variant names:

• chr7-37894544-T-C
• rs56128139
• NM_016616.5:c.1478T>C

Your query was ambiguous. Multiple possible variants found:

• chr7-37894544-T-C
• chr7-37894544-T-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016616.5(NME8):​c.1478T>C​(p.Ile493Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.32 in 1,607,030 control chromosomes in the GnomAD database, including 88,663 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. I493I) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.25 (6054 hom., cov: 32)
  • Exomes 𝑓: 0.33 (82609 hom.)
• Consequence: NME8 NM_016616.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0760
• Publications: 23 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

ENSG00000290149 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032392144).
• BP6: Variant 7-37894544-T-C is Benign according to our data. Variant chr7-37894544-T-C is described in ClinVar as Benign. ClinVar VariationId is 178811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016616.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NME8	NM_016616.5	MANE Select	c.1478T>C	p.Ile493Thr	missense	Exon 16 of 18	NP_057700.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NME8	ENST00000199447.9	TSL:1 MANE Select	c.1478T>C	p.Ile493Thr	missense	Exon 16 of 18	ENSP00000199447.4	Q8N427
	NME8	ENST00000440017.5	TSL:1	c.1478T>C	p.Ile493Thr	missense	Exon 15 of 16	ENSP00000397063.1	Q8N427
	ENSG00000290149	ENST00000476620.1	TSL:4	c.-38+37199T>C		intron	N/A	ENSP00000425858.1	D6RIH7

Frequencies

GnomAD3 genomes AF: 0.251 AC: 38051 AN: 151788 Hom.: 6053 Cov.: 32

Gnomad AFR AF: 0.0677

Gnomad AMI AF: 0.417

Gnomad AMR AF: 0.248

Gnomad ASJ AF: 0.306

Gnomad EAS AF: 0.137

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.361

Gnomad OTH AF: 0.276

GnomAD2 exomes AF: 0.273 AC: 68347 AN: 250580 AF XY: 0.273

Gnomad AFR exome AF: 0.0590

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: 476874 AN: 1455124 Hom.: 82609 Cov.: 34 AF XY: 0.324 AC XY: 234615 AN XY: 724196

African (AFR) AF: 0.0524 AC: 1751 AN: 33398

American (AMR) AF: 0.243 AC: 10818 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.300 AC: 7814 AN: 26042

East Asian (EAS) AF: 0.157 AC: 6235 AN: 39604

South Asian (SAS) AF: 0.167 AC: 14399 AN: 86130

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

Middle Eastern (MID) AF: 0.262 AC: 1500 AN: 5730

European-Non Finnish (NFE) AF: 0.360 AC: 397794 AN: 1106112

Other (OTH) AF: 0.312 AC: 18765 AN: 60132

GnomAD4 genome AF: 0.250 AC: 38041 AN: 151906 Hom.: 6054 Cov.: 32 AF XY: 0.246 AC XY: 18270 AN XY: 74258

African (AFR) AF: 0.0675 AC: 2800 AN: 41510

American (AMR) AF: 0.247 AC: 3773 AN: 15252

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

East Asian (EAS) AF: 0.137 AC: 705 AN: 5158

South Asian (SAS) AF: 0.162 AC: 779 AN: 4810

European-Finnish (FIN) AF: 0.323 AC: 3396 AN: 10526

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

European-Non Finnish (NFE) AF: 0.361 AC: 24502 AN: 67880

Other (OTH) AF: 0.272 AC: 574 AN: 2108

Alfa AF: 0.329 Hom.: 17722

Bravo AF: 0.240

TwinsUK AF: 0.362 AC: 1341

ALSPAC AF: 0.353 AC: 1360

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00896 AC: 77

ExAC AF: 0.268 AC: 32518

Asia WGS AF: 0.152 AC: 529 AN: 3472

EpiCase AF: 0.350

EpiControl AF: 0.343

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	not provided (1)
-	-	1	Primary ciliary dyskinesia (1)
-	-	1	Primary ciliary dyskinesia 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	6.8
DANN	Benign	0.59
DEOGEN2	Benign	0.019	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0011	N
LIST_S2	Benign	0.28	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.076
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.50	N
REVEL	Benign	0.068
Sift	Benign	0.032	D
Sift4G	Uncertain	0.040	D
Polyphen		0.010	B
Vest4		0.30
MPC		0.025
ClinPred		0.0019	T
GERP RS		1.1
Varity_R		0.064
gMVP		0.29
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs56128139; hg19: chr7-37934146; COSMIC: COSV52250919; COSMIC: COSV52250919;