14-67198297-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001395907.1(GARIN2):ā€‹c.136A>Gā€‹(p.Met46Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000034 ( 0 hom. )

Consequence

GARIN2
NM_001395907.1 missense

Scores

2
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.23
Variant links:
Genes affected
GARIN2 (HGNC:20101): (golgi associated RAB2 interactor family member 2)
GPHN (HGNC:15465): (gephyrin) This gene encodes a neuronal assembly protein that anchors inhibitory neurotransmitter receptors to the postsynaptic cytoskeleton via high affinity binding to a receptor subunit domain and tubulin dimers. In nonneuronal tissues, the encoded protein is also required for molybdenum cofactor biosynthesis. Mutations in this gene may be associated with the neurological condition hyperplexia and also lead to molybdenum cofactor deficiency. Numerous alternatively spliced transcript variants encoding different isoforms have been described; however, the full-length nature of all transcript variants is not currently known. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.08153522).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GARIN2NM_001395907.1 linkuse as main transcriptc.136A>G p.Met46Val missense_variant 3/8 ENST00000696955.1 NP_001382836.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GARIN2ENST00000696955.1 linkuse as main transcriptc.136A>G p.Met46Val missense_variant 3/8 NM_001395907.1 ENSP00000512992.1 A0A8V8TKJ2

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152122
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000385
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:
0.00000798
AC:
2
AN:
250634
Hom.:
0
AF XY:
0.00000739
AC XY:
1
AN XY:
135406
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
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:
0.00000342
AC:
5
AN:
1461356
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
726928
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000101
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:
0.0000131
AC:
2
AN:
152122
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74304
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000385
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000302
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 02, 2023The c.136A>G (p.M46V) alteration is located in exon 3 (coding exon 1) of the FAM71D gene. This alteration results from a A to G substitution at nucleotide position 136, causing the methionine (M) at amino acid position 46 to be replaced by a valine (V). 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
0.068
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
13
DANN
Benign
0.91
DEOGEN2
Benign
0.040
.;T;.
Eigen
Benign
-0.41
Eigen_PC
Benign
-0.27
FATHMM_MKL
Benign
0.67
D
LIST_S2
Benign
0.66
T;T;T
MetaRNN
Benign
0.082
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.0
.;M;.
PrimateAI
Benign
0.34
T
PROVEAN
Uncertain
-2.7
D;.;D
REVEL
Benign
0.079
Sift
Benign
0.24
T;.;T
Sift4G
Benign
0.30
T;T;T
Polyphen
0.0050
.;B;.
Vest4
0.27
MutPred
0.42
Gain of catalytic residue at M46 (P = 0.0107);Gain of catalytic residue at M46 (P = 0.0107);Gain of catalytic residue at M46 (P = 0.0107);
MVP
0.067
ClinPred
0.16
T
GERP RS
2.5
Varity_R
0.14
gMVP
0.20

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

LitVar

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

Other links and lift over

dbSNP: rs753771183; hg19: chr14-67665014; API