14-74855624-A-G

Variant names:

• chr14-74855624-A-G
• rs10483863
• NM_001243007.2:c.1609-322T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001243007.2(PROX2):​c.1609-322T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.561 in 213,920 control chromosomes in the GnomAD database, including 34,559 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.58 (25948 hom., cov: 34)
  • Exomes 𝑓: 0.52 (8611 hom.)
• Consequence: PROX2 NM_001243007.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.685
• Publications: 9 publications found

Genes affected

PROX2 (HGNC:26715): (prospero homeobox 2) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

YLPM1 (HGNC:17798): (YLP motif containing 1) Enables RNA binding activity. Predicted to be involved in regulation of telomere maintenance. Predicted to act upstream of or within negative regulation of transcription by RNA polymerase II. Located in cytosol and nuclear speck. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.717 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001243007.2. 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
	PROX2	NM_001243007.2	MANE Select	c.1609-322T>C		intron	N/A	NP_001229936.1	G3V3G0
	PROX2	NM_001384314.1		c.1609-322T>C		intron	N/A	NP_001371243.1	G3V3G0
	PROX2	NM_001080408.3		c.928-322T>C		intron	N/A	NP_001073877.2	Q3B8N5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROX2	ENST00000556489.4	TSL:1 MANE Select	c.1609-322T>C		intron	N/A	ENSP00000451223.2	G3V3G0
	YLPM1	ENST00000554107.2	TSL:3	c.*282A>G		3_prime_UTR	Exon 4 of 4	ENSP00000476212.1	U3KQT9
	PROX2	ENST00000673765.1		c.928-322T>C		intron	N/A	ENSP00000501015.1	Q3B8N5-2

Frequencies

GnomAD3 genomes AF: 0.575 AC: 87498 AN: 152052 Hom.: 25911 Cov.: 34

Gnomad AFR AF: 0.724

Gnomad AMI AF: 0.527

Gnomad AMR AF: 0.477

Gnomad ASJ AF: 0.499

Gnomad EAS AF: 0.404

Gnomad SAS AF: 0.602

Gnomad FIN AF: 0.642

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.514

Gnomad OTH AF: 0.553

GnomAD4 exome AF: 0.524 AC: 32368 AN: 61750 Hom.: 8611 Cov.: 0 AF XY: 0.524 AC XY: 16358 AN XY: 31216

African (AFR) AF: 0.719 AC: 1808 AN: 2514

American (AMR) AF: 0.495 AC: 1041 AN: 2102

Ashkenazi Jewish (ASJ) AF: 0.509 AC: 1423 AN: 2798

East Asian (EAS) AF: 0.478 AC: 2335 AN: 4880

South Asian (SAS) AF: 0.627 AC: 429 AN: 684

European-Finnish (FIN) AF: 0.623 AC: 1806 AN: 2900

Middle Eastern (MID) AF: 0.480 AC: 165 AN: 344

European-Non Finnish (NFE) AF: 0.513 AC: 21092 AN: 41150

Other (OTH) AF: 0.518 AC: 2269 AN: 4378

GnomAD4 genome AF: 0.576 AC: 87585 AN: 152170 Hom.: 25948 Cov.: 34 AF XY: 0.578 AC XY: 42989 AN XY: 74394

African (AFR) AF: 0.724 AC: 30061 AN: 41516

American (AMR) AF: 0.477 AC: 7283 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.499 AC: 1731 AN: 3472

East Asian (EAS) AF: 0.405 AC: 2098 AN: 5180

South Asian (SAS) AF: 0.601 AC: 2897 AN: 4822

European-Finnish (FIN) AF: 0.642 AC: 6801 AN: 10586

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.514 AC: 34921 AN: 67996

Other (OTH) AF: 0.554 AC: 1169 AN: 2110

Alfa AF: 0.513 Hom.: 12343

Bravo AF: 0.567

Asia WGS AF: 0.547 AC: 1901 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.2
DANN	Benign	0.75
PhyloP100		-0.69
Mutation Taster		=100/0	polymorphism (auto)

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: rs10483863; hg19: chr14-75322327;