chr5-77630607-G-A

Position:

• chr5-77630607-G-A

Variant summary

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

The NM_032109.3(OTP):​c.635C>T​(p.Ala212Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000286 in 1,400,470 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: OTP NM_032109.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.94

Genes affected

OTP (HGNC:8518): (orthopedia homeobox) This gene encodes a member of the homeodomain (HD) family. HD family proteins are helix-turn-helix transcription factors that play key roles in the specification of cell fates. This protein may function during brain development. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTP	NM_032109.3	c.635C>T	p.Ala212Val	missense_variant	3/3	ENST00000306422.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTP	ENST00000306422.5	c.635C>T	p.Ala212Val	missense_variant	3/3	1	NM_032109.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000286 AC: 4 AN: 1400470 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 692880

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: 0.00000368

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000284 AC: 3

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

May 10, 2022

The c.635C>T (p.A212V) alteration is located in exon 3 (coding exon 3) of the OTP gene. This alteration results from a C to T substitution at nucleotide position 635, causing the alanine (A) at amino acid position 212 to be replaced by a valine (V). 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	0.23
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.62
Sift	Benign	0.21	T
Sift4G	Uncertain	0.031	D
Polyphen		0.99	D
Vest4		0.40
MutPred		0.43		Loss of disorder (P = 0.0533);
MVP		0.66
MPC		1.4
ClinPred		0.98	D
GERP RS		3.6
Varity_R		0.27
gMVP		0.86

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

LitVar

Other links and lift over

dbSNP: rs759599725; hg19: chr5-76926432;