Genetic Variant NM_018982.5:c.832G>C (chr1-53860153-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_018982.5(YIPF1):c.832G>C(p.Ala278Pro) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000384 in 1,613,526 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 1 hom. )

Consequence

YIPF1
NM_018982.5 missense, splice_region

Scores

Splicing: ADA: 0.9990

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.84

Variant links:

Genes affected

YIPF1 (HGNC:25231): (Yip1 domain family member 1) Predicted to enable small GTPase binding activity. Predicted to be involved in vesicle-mediated transport. Located in several cellular components, including Golgi apparatus subcompartment; nucleoplasm; and transport vesicle. [provided by Alliance of Genome Resources, Apr 2022]

YIPF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
YIPF1	NM_018982.5 link	c.832G>C	p.Ala278Pro	missense_variant, splice_region_variant	Exon 10 of 11	ENST00000072644.7	NP_061855.1	Q9Y548-1
YIPF1	NR_036639.2 link	n.1186G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 10 of 12
YIPF1	NR_036640.2 link	n.966G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 9 of 11
YIPF1	NR_135075.2 link	n.886G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 8 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
YIPF1	ENST00000072644.7 link	c.832G>C	p.Ala278Pro	missense_variant, splice_region_variant	Exon 10 of 11	1	NM_018982.5	ENSP00000072644.1	Q9Y548-1
YIPF1	ENST00000464950.6 link	n.832G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 9 of 11	1		ENSP00000432266.1	Q9Y548-1
YIPF1	ENST00000371399.5 link	c.283G>C	p.Ala95Pro	missense_variant, splice_region_variant	Exon 8 of 9	2		ENSP00000360452.1	Q9Y548-2

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

151998

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000187

AC:

AN:

251164

Hom.:

AF XY:

0.000147

AC XY:

AN XY:

135732

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00133

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000383

AC:

AN:

1461410

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727044

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00121

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

AF:

0.0000394

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000140

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000115

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 20, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.832G>C (p.A278P) alteration is located in exon 10 (coding exon 8) of the YIPF1 gene. This alteration results from a G to C substitution at nucleotide position 832, causing the alanine (A) at amino acid position 278 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

0.80

BayesDel_addAF

Uncertain

0.092

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.090

.;T

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

D;D

M_CAP

Benign

0.0038

MetaRNN

Benign

0.22

T;T

MetaSVM

Benign

-0.57

MutationAssessor

Benign

2.0

.;M

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.9

N;N

REVEL

Uncertain

0.32

Sift

Benign

0.050

D;D

Sift4G

Uncertain

0.023

D;D

Polyphen

0.97

.;D

Vest4

0.87

MVP

0.17

MPC

0.11

ClinPred

0.14

GERP RS

5.1

Varity_R

0.59

gMVP

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.90

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over