chr16-4694197-G-A

Variant names:

• chr16-4694197-G-A
• rs754321966
• NM_032349.4:c.373G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032349.4(NUDT16L1):​c.373G>A​(p.Val125Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NUDT16L1 NM_032349.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.46

Genes affected

NUDT16L1 (HGNC:28154): (nudix hydrolase 16 like 1) Enables snoRNA binding activity. Involved in negative regulation of double-strand break repair via nonhomologous end joining. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12399304).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUDT16L1	NM_032349.4	c.373G>A	p.Val125Met	missense_variant	Exon 2 of 3	ENST00000304301.11	NP_115725.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NUDT16L1	ENST00000304301.11	c.373G>A	p.Val125Met	missense_variant	Exon 2 of 3	1	NM_032349.4	ENSP00000306670.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1408130 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 698552

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000873 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.373G>A (p.V125M) alteration is located in exon 2 (coding exon 2) of the NUDT16L1 gene. This alteration results from a G to A substitution at nucleotide position 373, causing the valine (V) at amino acid position 125 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;.;T;.
Eigen	Benign	-0.029
Eigen_PC	Benign	-0.035
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Uncertain	0.29	D
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-0.92	T
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-2.2	N;.;.;.
REVEL	Benign	0.046
Sift	Uncertain	0.0030	D;.;.;.
Sift4G	Uncertain	0.011	D;D;D;D
Polyphen		0.73	P;.;.;D
Vest4		0.57
MutPred		0.33		Gain of catalytic residue at V125 (P = 0.0748);Gain of catalytic residue at V125 (P = 0.0748);Gain of catalytic residue at V125 (P = 0.0748);Gain of catalytic residue at V125 (P = 0.0748);
MVP		0.34
MPC		0.58
ClinPred		0.68	D
GERP RS		2.9
Varity_R		0.39
gMVP		0.62

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: rs754321966; hg19: chr16-4744198;