Genetic Variant NM_001308429.2:c.673G>A (chr19-50467696-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001308429.2(GARIN5A):c.673G>A(p.Gly225Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000282 in 1,593,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign 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. G225D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

GARIN5A
NM_001308429.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.882

Publications

0 publications found

Variant links:

Genes affected

GARIN5A (HGNC:25107): (golgi associated RAB2 interactor 5A)

GARIN5A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.055158287).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARIN5A	NM_001308429.2 link	c.673G>A	p.Gly225Ser	missense_variant	Exon 4 of 5	ENST00000600100.6	NP_001295358.1	Q6IPT2-1
GARIN5A	NM_138411.3 link	c.625G>A	p.Gly209Ser	missense_variant	Exon 4 of 5		NP_612420.1	Q6IPT2-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GARIN5A	ENST00000600100.6 link	c.673G>A	p.Gly225Ser	missense_variant	Exon 4 of 5	1	NM_001308429.2	ENSP00000472421.2		Q6IPT2-1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000751

AC:

AN:

213102

AF XY:

0.0000781

show subpopulations

Gnomad AFR exome

AF:

0.000155

Gnomad AMR exome

AF:

0.000394

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000213

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000194

AC:

AN:

1441190

Hom.:

Cov.:

AF XY:

0.0000196

AC XY:

AN XY:

715082

show subpopulations

African (AFR)

AF:

0.000181

AC:

AN:

33136

American (AMR)

AF:

0.000339

AC:

AN:

41252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25734

East Asian (EAS)

AF:

0.00

AC:

AN:

38662

South Asian (SAS)

AF:

0.00

AC:

AN:

83306

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51686

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.00000544

AC:

AN:

1102114

Other (OTH)

AF:

0.0000336

AC:

AN:

59562

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000112

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.000290

AC:

AN:

41432

American (AMR)

AF:

0.0000654

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000340

Hom.:

Bravo

AF:

0.000110

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000413

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 19, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.625G>A (p.G209S) alteration is located in exon 4 (coding exon 4) of the FAM71E1 gene. This alteration results from a G to A substitution at nucleotide position 625, causing the glycine (G) at amino acid position 209 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

Benign

0.17

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0031

T;.

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.68

T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.055

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.64

N;.

PhyloP100

0.88

PrimateAI

Benign

0.44

Sift4G

Benign

0.19

T;T

Polyphen

0.99

D;D

Vest4

0.23

MVP

0.12

MPC

0.61

ClinPred

0.14

GERP RS

1.8

Varity_R

0.066

gMVP

0.41

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over