Genetic Variant GARIN4:p.Pro44Ser (chr1-212625007-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_153606.4(GARIN4):c.130C>T(p.Pro44Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P44L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

GARIN4
NM_153606.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.27

Variant links:

Genes affected

GARIN4 (HGNC:26541): (golgi associated RAB2 interactor family member 4) This gene encodes a protein that interacts with the Rab2B small GTPase and may be important for integrity of the Golgi body. A knockdown of this gene induces fragmentation of the Golgi, similar to the effect seen with a knockdown of the Rab2B small GTPase. The encoded protein has an N-terminal Rab-binding domain specific for Rab2B. [provided by RefSeq, Feb 2017]

GARIN4 links:

ENSG00000235862 (HGNC:):

ENSG00000235862 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.914

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARIN4	NM_153606.4 link	c.130C>T	p.Pro44Ser	missense_variant	Exon 1 of 1	ENST00000294829.5	NP_705834.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GARIN4	ENST00000294829.5 link	c.130C>T	p.Pro44Ser	missense_variant	Exon 1 of 1	6	NM_153606.4	ENSP00000294829.3		Q8IYT1
ENSG00000235862	ENST00000427949.1 link	n.1539-37G>A		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000795

AC:

AN:

251486

AF XY:

0.0000147

show subpopulations

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000126

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 04, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.130C>T (p.P44S) alteration is located in exon 1 (coding exon 1) of the FAM71A gene. This alteration results from a C to T substitution at nucleotide position 130, causing the proline (P) at amino acid position 44 to be replaced by a serine (S). 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

0.63

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.010

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.21

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.81

M_CAP

Benign

0.0027

MetaRNN

Pathogenic

0.91

MetaSVM

Benign

-0.99

MutationAssessor

Pathogenic

3.3

PhyloP100

2.3

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-7.7

REVEL

Benign

0.22

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.013

Polyphen

1.0

Vest4

0.66

MutPred

0.83

Gain of sheet (P = 0.0827);

MVP

0.27

MPC

0.41

ClinPred

0.98

GERP RS

4.6

Varity_R

0.60

gMVP

0.37

Mutation Taster

=81/19

polymorphism

(source)

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

Publications

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chr1-212625007-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

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