10-119030177-G-A

Variant summary

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

The NM_199461.4(NANOS1):c.376G>A(p.Ala126Thr) 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. 13/20 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NANOS1 NM_199461.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.19

Genes affected

NANOS1 (HGNC:23044): (nanos C2HC-type zinc finger 1) This gene encodes a CCHC-type zinc finger protein that is a member of the nanos family. This protein co-localizes with the RNA-binding protein pumilio RNA-binding family member 2 and may be involved in regulating translation as a post-transcriptional repressor. Mutations in this gene are associated with spermatogenic impairment. [provided by RefSeq, Sep 2015]

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=0.25281554).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NANOS1	NM_199461.4	c.376G>A	p.Ala126Thr	missense_variant	1/1	ENST00000425699.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NANOS1	ENST00000425699.3	c.376G>A	p.Ala126Thr	missense_variant	1/1		NM_199461.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1192822 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 582066

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.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2023

The c.376G>A (p.A126T) alteration is located in exon 1 (coding exon 1) of the NANOS1 gene. This alteration results from a G to A substitution at nucleotide position 376, causing the alanine (A) at amino acid position 126 to be replaced by a threonine (T). 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	0.14
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.46	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	0.98	N
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.11
Sift	Benign	0.20	T
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.12
MutPred		0.21		Gain of loop (P = 0.0435);
MVP		0.55
ClinPred		0.74	D
GERP RS		3.7
Varity_R		0.13
gMVP		0.33

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-120789689;