chr5-77630740-C-A

Variant names:

• chr5-77630740-C-A
• rs769791656
• NM_032109.3:c.502G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_032109.3(OTP):​c.502G>T​(p.Val168Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,428,960 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. V168M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: OTP NM_032109.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.51
• Publications: 0 publications found

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]

OTP-AS1 (HGNC:):

OTP-AS1 (HGNC:58154):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21541712).
• BS2: High AC in GnomAdExome4 at 23 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032109.3. 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
	OTP	NM_032109.3	MANE Select	c.502G>T	p.Val168Leu	missense	Exon 3 of 3	NP_115485.1	Q5XKR4
	OTP-AS1	NR_198942.1		n.91+979C>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTP	ENST00000306422.5	TSL:1 MANE Select	c.502G>T	p.Val168Leu	missense	Exon 3 of 3	ENSP00000302814.3	Q5XKR4
	OTP-AS1	ENST00000851058.1		n.91+979C>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000397 AC: 8 AN: 201620 AF XY: 0.0000530

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000161 AC: 23 AN: 1428960 Hom.: 0 Cov.: 30 AF XY: 0.0000225 AC XY: 16 AN XY: 710304

African (AFR) AF: 0.00 AC: 0 AN: 32372

American (AMR) AF: 0.00 AC: 0 AN: 41034

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25318

East Asian (EAS) AF: 0.00 AC: 0 AN: 39076

South Asian (SAS) AF: 0.000261 AC: 22 AN: 84384

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104372

Other (OTH) AF: 0.0000168 AC: 1 AN: 59394

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000341 AC: 4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Benign	0.076
Eigen_PC	Benign	0.054
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.22	T
MetaSVM	Uncertain	-0.0044	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.5
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.38
Sift	Benign	0.098	T
Sift4G	Benign	0.15	T
Polyphen		0.90	P
Vest4		0.22
MutPred		0.33		Loss of methylation at K164 (P = 0.0679)
MVP		0.70
MPC		0.84
ClinPred		0.28	T
GERP RS		2.5
Varity_R		0.21
gMVP		0.80
Mutation Taster		=82/18	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: rs769791656; hg19: chr5-76926565;