NM_016616.5:c.1405A>C

Variant names:

• chr7-37894471-A-C
• rs147791304
• NM_016616.5:c.1405A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_016616.5(NME8):​c.1405A>C​(p.Ile469Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000462 in 1,612,772 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I469V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: NME8 NM_016616.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.82
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014408082).
• BP6: Variant 7-37894471-A-C is Benign according to our data. Variant chr7-37894471-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1405A>C	p.Ile469Leu	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.1405A>C	p.Ile469Leu	missense	Exon 16 of 18	ENSP00000199447.4	Q8N427
	NME8	ENST00000440017.5	TSL:1	c.1405A>C	p.Ile469Leu	missense	Exon 15 of 16	ENSP00000397063.1	Q8N427
	ENSG00000290149	ENST00000476620.1	TSL:4	c.-38+37126A>C		intron	N/A	ENSP00000425858.1	D6RIH7

Frequencies

GnomAD3 genomes AF: 0.00241 AC: 366 AN: 152146 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00838

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000726 AC: 182 AN: 250768 AF XY: 0.000494

Gnomad AFR exome AF: 0.00985

Gnomad AMR exome AF: 0.000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000259 AC: 379 AN: 1460508 Hom.: 0 Cov.: 31 AF XY: 0.000205 AC XY: 149 AN XY: 726596

African (AFR) AF: 0.00931 AC: 311 AN: 33402

American (AMR) AF: 0.000560 AC: 25 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39604

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5756

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111064

Other (OTH) AF: 0.000547 AC: 33 AN: 60324

GnomAD4 genome AF: 0.00240 AC: 366 AN: 152264 Hom.: 1 Cov.: 33 AF XY: 0.00234 AC XY: 174 AN XY: 74450

African (AFR) AF: 0.00835 AC: 347 AN: 41554

American (AMR) AF: 0.000850 AC: 13 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68000

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00105 Hom.: 1

Bravo AF: 0.00269

ESP6500AA AF: 0.00772 AC: 34

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000750 AC: 91

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely 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	0.27
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.014	T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		5.8
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.40
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.081	T
Polyphen		0.98	D
Vest4		0.70
MVP		0.60
MPC		0.11
ClinPred		0.057	T
GERP RS		4.0
Varity_R		0.31
gMVP		0.61
Mutation Taster		=90/10	polymorphism

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: rs147791304; hg19: chr7-37934073;