rs985108625

Variant names:

• chr7-25225145-C-T
• rs985108625
• NM_022150.3:c.568G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022150.3(NPVF):​c.568G>A​(p.Ala190Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NPVF NM_022150.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.202
• Publications: 0 publications found

Genes affected

NPVF (HGNC:13782): (neuropeptide VF precursor) Predicted to enable signaling receptor binding activity. Involved in negative regulation of gonadotropin secretion. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.047759473).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022150.3. 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
	NPVF	NM_022150.3	MANE Select	c.568G>A	p.Ala190Thr	missense	Exon 3 of 3	NP_071433.3	Q9HCQ7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPVF	ENST00000222674.2	TSL:1 MANE Select	c.568G>A	p.Ala190Thr	missense	Exon 3 of 3	ENSP00000222674.2	Q9HCQ7-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461414 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 727044

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33422

American (AMR) AF: 0.00 AC: 0 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111822

Other (OTH) AF: 0.00 AC: 0 AN: 60368

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000096912), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	7.7
DANN	Uncertain	0.98
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.064	N
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.20
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.036
Sift	Benign	0.079	T
Sift4G	Benign	0.13	T
Vest4		0.096
MutPred		0.11		Gain of phosphorylation at A190 (P = 0.0227)
MVP		0.014
MPC		0.046
ClinPred		0.13	T
GERP RS		1.7
gMVP		0.056
Mutation Taster		=93/7	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: rs985108625; hg19: chr7-25264764; COSMIC: COSV99033657;