2-216859687-T-C

Variant names:

• chr2-216859687-T-C
• rs760854000
• NM_003284.4:c.148A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003284.4(TNP1):​c.148A>G​(p.Asn50Asp) 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. 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)
• Consequence: TNP1 NM_003284.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.05

Genes affected

TNP1 (HGNC:11951): (transition protein 1) Transition protein-1 is a spermatid-specific product of the haploid genome which replaces histone and is itself replaced in the mature sperm by the protamines (see PRM1, MIM 182880; PRM2, MIM 182890) (Luerssen et al., 1990 [PubMed 2249851]).[supplied by OMIM, Mar 2008]

TESHL (HGNC:52740): (testicular germ cell expressed HSF2 interacting lncRNA)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33991683).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNP1	NM_003284.4	c.148A>G	p.Asn50Asp	missense_variant	Exon 2 of 2	ENST00000236979.2	NP_003275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNP1	ENST00000236979.2	c.148A>G	p.Asn50Asp	missense_variant	Exon 2 of 2	1	NM_003284.4	ENSP00000236979.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000540 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.148A>G (p.N50D) alteration is located in exon 2 (coding exon 2) of the TNP1 gene. This alteration results from a A to G substitution at nucleotide position 148, causing the asparagine (N) at amino acid position 50 to be replaced by an aspartic acid (D). 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	0.28
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-0.060
Eigen_PC	Benign	0.016
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.98	T
PhyloP100		2.1
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.094
Sift	Uncertain	0.016	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.32	B
Vest4		0.32
MutPred		0.41		Loss of stability (P = 0.0742);
MVP		0.18
MPC		0.25
ClinPred		0.62	D
GERP RS		4.1
PromoterAI		-0.0050	Neutral
Varity_R		0.32
gMVP		0.037
Mutation Taster		=95/5	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

Publications

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Other links and lift over

dbSNP: rs760854000; hg19: chr2-217724410;