9-137192674-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001128228.3(TPRN):c.1743C>G(p.Asn581Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. N581S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TPRN NM_001128228.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.78

Genes affected

TPRN (HGNC:26894): (taperin) This locus encodes a sensory epithelial protein. It was defined by linkage analysis in three Pakistani families to lie between D9S1818 (centromeric) and D9SH6 (telomeric). Mutations at this locus have been associated with autosomal recessive deafness. [provided by RefSeq, Oct 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.369708).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPRN	NM_001128228.3	c.1743C>G	p.Asn581Lys	missense_variant	2/4	ENST00000409012.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPRN	ENST00000409012.6	c.1743C>G	p.Asn581Lys	missense_variant	2/4	1	NM_001128228.3	P1
TPRN	ENST00000477345.1	n.2464C>G		non_coding_transcript_exon_variant	1/3	1
TPRN	ENST00000333046.8	c.1137C>G	p.Asn379Lys	missense_variant	2/3	2
TPRN	ENST00000541945.1	n.108C>G		non_coding_transcript_exon_variant	2/2	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 248342 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134664

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000901

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461482 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727046

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	12
Dann	Uncertain	0.98
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.63	T;T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Benign	-0.34	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Benign	0.27
Sift	Uncertain	0.0030	D;D
Sift4G	Benign	0.11	T;D
Polyphen		1.0	.;D
Vest4		0.79
MutPred		0.34		.;Gain of methylation at N581 (P = 5e-04);
MVP		0.030
ClinPred		0.94	D
GERP RS		-6.7
Varity_R		0.53
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs146518581; hg19: chr9-140087126;