Genetic Variant YIPF3:p.Pro146Ala (chr6-43513593-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015388.4(YIPF3):c.436C>G(p.Pro146Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000699 in 1,430,246 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P146S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

YIPF3
NM_015388.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.17

Publications

0 publications found

Variant links:

Genes affected

YIPF3 (HGNC:21023): (Yip1 domain family member 3) Predicted to be involved in cell differentiation. Located in Golgi apparatus and transport vesicle. [provided by Alliance of Genome Resources, Apr 2022]

YIPF3 links:

POLR1C (HGNC:20194): (RNA polymerase I and III subunit C) The protein encoded by this gene is a subunit of both RNA polymerase I and RNA polymerase III complexes. The encoded protein is part of the Pol core element. Mutations in this gene have been associated with Treacher Collins syndrome (TCS) and hypomyelinating leukodystrophy 11. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

POLR1C Gene-Disease associations (from GenCC):

hypomyelinating leukodystrophy 11
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
Treacher Collins syndrome 3
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
Treacher-Collins syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

POLR1C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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
YIPF3	NM_015388.4 link	c.436C>G	p.Pro146Ala	missense_variant	Exon 4 of 9	ENST00000372422.7	NP_056203.2	Q9GZM5
YIPF3	XM_047418608.1 link	c.331C>G	p.Pro111Ala	missense_variant	Exon 4 of 9		XP_047274564.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
YIPF3	ENST00000372422.7 link	c.436C>G	p.Pro146Ala	missense_variant	Exon 4 of 9	1	NM_015388.4	ENSP00000361499.2		Q9GZM5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.99e-7

AC:

AN:

1430246

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

708290

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32596

American (AMR)

AF:

0.00

AC:

AN:

41246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23704

East Asian (EAS)

AF:

0.00

AC:

AN:

39470

South Asian (SAS)

AF:

0.0000123

AC:

AN:

81098

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52012

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5588

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1095568

Other (OTH)

AF:

0.00

AC:

AN:

58964

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Benign

0.0083

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

T;T;T

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Benign

0.019

MetaRNN

Uncertain

0.74

D;D;D

MetaSVM

Benign

-0.64

MutationAssessor

Uncertain

2.1

M;.;.

PhyloP100

7.2

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-2.7

D;D;D

REVEL

Uncertain

0.31

Sift

Benign

0.032

D;D;D

Sift4G

Uncertain

0.040

D;D;.

Polyphen

0.99

D;D;.

Vest4

0.64

MutPred

0.76

.;Loss of loop (P = 0.0128);.;

MVP

0.068

MPC

0.66

ClinPred

0.80

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.20

gMVP

0.65

Mutation Taster

=42/58

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over