1-212625134-T-C

Variant names:

• chr1-212625134-T-C
• rs958728705
• NM_153606.4:c.257T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_153606.4(GARIN4):​c.257T>C​(p.Met86Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. M86I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: GARIN4 NM_153606.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.81

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]

ENSG00000235862 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.796

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARIN4	NM_153606.4	c.257T>C	p.Met86Thr	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	c.257T>C	p.Met86Thr	missense_variant	Exon 1 of 1	6	NM_153606.4	ENSP00000294829.3
ENSG00000235862	ENST00000427949.1	n.1538+100A>G		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.257T>C (p.M86T) alteration is located in exon 1 (coding exon 1) of the FAM71A gene. This alteration results from a T to C substitution at nucleotide position 257, causing the methionine (M) at amino acid position 86 to be replaced by a threonine (T). 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	0.96
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.0030	T
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.93	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		3.8
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Benign	0.16
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.45		Gain of glycosylation at M86 (P = 0.0263);
MVP		0.36
MPC		0.42
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.73
gMVP		0.38
Mutation Taster		=85/15	polymorphism

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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Other links and lift over

dbSNP: rs958728705; hg19: chr1-212798476;