7-37850665-G-A

Variant names:

• chr7-37850665-G-A
• rs2722372
• NM_016616.5:c.128G>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.128G>A​(p.Arg43Lys) variant causes a missense change. The variant allele was found at a frequency of 0.244 in 1,607,830 control chromosomes in the GnomAD database, including 50,097 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6015 hom., cov: 33)
  • Exomes 𝑓: 0.24 (44082 hom.)
• Consequence: NME8 NM_016616.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.05
• Publications: 29 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=0.0029492974).
• BP6: Variant 7-37850665-G-A is Benign according to our data. Variant chr7-37850665-G-A is described in ClinVar as Benign. ClinVar VariationId is 164798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.361 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.128G>A	p.Arg43Lys	missense	Exon 5 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.128G>A	p.Arg43Lys	missense	Exon 5 of 18	ENSP00000199447.4	Q8N427
	NME8	ENST00000440017.5	TSL:1	c.128G>A	p.Arg43Lys	missense	Exon 4 of 16	ENSP00000397063.1	Q8N427
	ENSG00000290149	ENST00000476620.1	TSL:4	c.-109-6609G>A		intron	N/A	ENSP00000425858.1	D6RIH7

Frequencies

GnomAD3 genomes AF: 0.275 AC: 41829 AN: 152060 Hom.: 6004 Cov.: 33

Gnomad AFR AF: 0.365

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.280

Gnomad EAS AF: 0.180

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.246

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.249

Gnomad OTH AF: 0.257

GnomAD2 exomes AF: 0.229 AC: 57551 AN: 251018 AF XY: 0.224

Gnomad AFR exome AF: 0.375

Gnomad AMR exome AF: 0.203

Gnomad ASJ exome AF: 0.282

Gnomad EAS exome AF: 0.185

Gnomad FIN exome AF: 0.236

Gnomad NFE exome AF: 0.243

Gnomad OTH exome AF: 0.236

GnomAD4 exome AF: 0.241 AC: 351025 AN: 1455654 Hom.: 44082 Cov.: 32 AF XY: 0.238 AC XY: 172701 AN XY: 724522

African (AFR) AF: 0.370 AC: 12347 AN: 33332

American (AMR) AF: 0.207 AC: 9240 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.281 AC: 7345 AN: 26102

East Asian (EAS) AF: 0.183 AC: 7252 AN: 39684

South Asian (SAS) AF: 0.138 AC: 11866 AN: 86164

European-Finnish (FIN) AF: 0.235 AC: 12559 AN: 53394

Middle Eastern (MID) AF: 0.239 AC: 1368 AN: 5730

European-Non Finnish (NFE) AF: 0.248 AC: 274468 AN: 1106358

Other (OTH) AF: 0.242 AC: 14580 AN: 60176

GnomAD4 genome AF: 0.275 AC: 41870 AN: 152176 Hom.: 6015 Cov.: 33 AF XY: 0.272 AC XY: 20226 AN XY: 74406

African (AFR) AF: 0.366 AC: 15168 AN: 41496

American (AMR) AF: 0.250 AC: 3816 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.280 AC: 972 AN: 3470

East Asian (EAS) AF: 0.181 AC: 937 AN: 5186

South Asian (SAS) AF: 0.136 AC: 656 AN: 4826

European-Finnish (FIN) AF: 0.246 AC: 2602 AN: 10590

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.249 AC: 16949 AN: 68012

Other (OTH) AF: 0.256 AC: 541 AN: 2110

Alfa AF: 0.256 Hom.: 11144

Bravo AF: 0.277

TwinsUK AF: 0.257 AC: 954

ALSPAC AF: 0.255 AC: 983

ESP6500AA AF: 0.369 AC: 1624

ESP6500EA AF: 0.243 AC: 2090

ExAC AF: 0.230 AC: 27946

Asia WGS AF: 0.164 AC: 571 AN: 3478

EpiCase AF: 0.246

EpiControl AF: 0.246

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	16
DANN	Benign	0.83
DEOGEN2	Benign	0.0024	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.16	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.3	N
PhyloP100		4.1
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.13
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.13
MPC		0.021
ClinPred		0.0072	T
GERP RS		3.9
Varity_R		0.091
gMVP		0.28
Mutation Taster		=99/1	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: rs2722372; hg19: chr7-37890267; COSMIC: COSV52246420;