rs199621229

chr7-37896968-C-Achr7-37896968-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016616.5(NME8):c.1643C>A(p.Ser548Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S548F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: NME8 NM_016616.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.761

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28005716).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NME8	NM_016616.5	c.1643C>A	p.Ser548Tyr	missense_variant	17/18	ENST00000199447.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NME8	ENST00000199447.9	c.1643C>A	p.Ser548Tyr	missense_variant	17/18	1	NM_016616.5	P1
NME8	ENST00000440017.5	c.1643C>A	p.Ser548Tyr	missense_variant	16/16	1		P1
NME8	ENST00000476435.1	n.152C>A		non_coding_transcript_exon_variant	1/2	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251194 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461654 Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6 AN XY: 727122

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	21
Dann	Benign	0.97
DEOGEN2	Benign	0.0093	T;T
Eigen	Benign	0.051
Eigen_PC	Benign	0.011
FATHMM_MKL	Benign	0.26	N
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Benign	0.19
Sift	Benign	0.39	T;T
Sift4G	Benign	0.10	T;T
Polyphen		0.54	P;P
Vest4		0.26
MutPred		0.50		Loss of disorder (P = 0.0079);Loss of disorder (P = 0.0079);
MVP		0.67
MPC		0.089
ClinPred		0.37	T
GERP RS		5.5
Varity_R		0.16
gMVP		0.25

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

Publications

LitVar

Other links and lift over

dbSNP: rs199621229; hg19: chr7-37936570;