5-144162251-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_030799.9(YIPF5):c.578T>C(p.Leu193Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,742 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: YIPF5 NM_030799.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.29

Genes affected

YIPF5 (HGNC:24877): (Yip1 domain family member 5) Predicted to be involved in endoplasmic reticulum to Golgi vesicle-mediated transport; regulation of ER to Golgi vesicle-mediated transport; and vesicle fusion with Golgi apparatus. Located in Golgi apparatus; endoplasmic reticulum; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a chain Protein YIPF5 (size 256) in uniprot entity YIPF5_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_030799.9
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
YIPF5	NM_030799.9	c.578T>C	p.Leu193Pro	missense_variant	5/6	ENST00000274496.10
YIPF5	NM_001024947.4	c.578T>C	p.Leu193Pro	missense_variant	5/6
YIPF5	NM_001271732.2	c.416T>C	p.Leu139Pro	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
YIPF5	ENST00000274496.10	c.578T>C	p.Leu193Pro	missense_variant	5/6	1	NM_030799.9	P1
YIPF5	ENST00000448443.6	c.578T>C	p.Leu193Pro	missense_variant	5/6	1		P1
YIPF5	ENST00000513112.5	c.416T>C	p.Leu139Pro	missense_variant	4/5	1
YIPF5	ENST00000519064.5	c.416T>C	p.Leu139Pro	missense_variant	4/5	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251288 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135816

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461742 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727182

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

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

Jan 17, 2024

The c.578T>C (p.L193P) alteration is located in exon 5 (coding exon 4) of the YIPF5 gene. This alteration results from a T to C substitution at nucleotide position 578, causing the leucine (L) at amino acid position 193 to be replaced by a proline (P). 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	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.14
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.088	T;T;.;T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.68	D;D;D;D
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.8	L;L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.0	D;D;D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0050	D;D;D;D
Sift4G	Uncertain	0.013	D;D;D;D
Polyphen		0.29	B;B;.;.
Vest4		0.95
MutPred		0.56		Loss of stability (P = 0.0418);Loss of stability (P = 0.0418);.;.;
MVP		0.82
MPC		0.27
ClinPred		0.90	D
GERP RS		5.7
Varity_R		0.84
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs753295519; hg19: chr5-143541815;