chr2-99018239-T-A

Variant names:

• chr2-99018239-T-A
• rs538067299
• NM_025244.4:c.2033A>T

Variant summary

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

The NM_025244.4(TSGA10):​c.2033A>T​(p.His678Leu) 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. 15/22 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. H678R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSGA10 NM_025244.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.18
• Publications: 1 publications found

Genes affected

TSGA10 (HGNC:14927): (testis specific 10) Predicted to enable structural molecule activity. Predicted to be involved in spermatogenesis. Predicted to act upstream of or within cell projection assembly. Predicted to be located in neuron projection; sperm fibrous sheath; and sperm principal piece. Implicated in spermatogenic failure 26. [provided by Alliance of Genome Resources, Apr 2022]

TSGA10 Gene-Disease associations (from GenCC):

• spermatogenic failure 26

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

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=0.053937405).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025244.4. 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
	TSGA10	NM_025244.4	MANE Select	c.2033A>T	p.His678Leu	missense	Exon 20 of 21	NP_079520.1	A0A218MIY9
	TSGA10	NM_001349012.1		c.2033A>T	p.His678Leu	missense	Exon 18 of 19	NP_001335941.1	A0A218MIY9
	TSGA10	NM_182911.4		c.2033A>T	p.His678Leu	missense	Exon 19 of 20	NP_878915.2	A0A218MIY9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSGA10	ENST00000393483.8	TSL:1 MANE Select	c.2033A>T	p.His678Leu	missense	Exon 20 of 21	ENSP00000377123.3	Q9BZW7-1
	TSGA10	ENST00000355053.8	TSL:1	c.2033A>T	p.His678Leu	missense	Exon 19 of 20	ENSP00000347161.4	Q9BZW7-1
	TSGA10	ENST00000410001.5	TSL:1	c.2033A>T	p.His678Leu	missense	Exon 18 of 19	ENSP00000386956.1	Q9BZW7-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251458 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.2
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.046
Sift	Benign	1.0	T
Sift4G	Benign	0.72	T
Polyphen		0.039	B
Vest4		0.38
MutPred		0.17		Loss of catalytic residue at H678 (P = 0.1973)
MVP		0.068
MPC		0.15
ClinPred		0.29	T
GERP RS		3.9
Varity_R		0.12
gMVP		0.22
Mutation Taster		=87/13	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: rs538067299; hg19: chr2-99634702;