1-212624978-A-C

Position:

• chr1-212624978-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_153606.4(GARIN4):​c.101A>C​(p.Lys34Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GARIN4 NM_153606.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.29

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]

(HGNC:):

ACMG classification

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=0.25129363).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GARIN4	NM_153606.4	c.101A>C	p.Lys34Thr	missense_variant	1/1	ENST00000294829.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GARIN4	ENST00000294829.5	c.101A>C	p.Lys34Thr	missense_variant	1/1		NM_153606.4	P1
	ENST00000427949.1	n.1539-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

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 Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 05, 2023

The c.101A>C (p.K34T) alteration is located in exon 1 (coding exon 1) of the FAM71A gene. This alteration results from a A to C substitution at nucleotide position 101, causing the lysine (K) at amino acid position 34 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	Benign	0.31
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.1	M
MutationTaster	Benign	0.71	N
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Benign	0.057
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.34
MutPred		0.30		Loss of methylation at K34 (P = 0.0096);
MVP		0.27
MPC		0.21
ClinPred		0.98	D
GERP RS		3.5
Varity_R		0.27
gMVP		0.23

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

Other links and lift over

dbSNP: rs111627662; hg19: chr1-212798320;