Genetic Variant FAM91A1:p.Arg154Gly (chr8-123778683-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_144963.4(FAM91A1):c.460C>G(p.Arg154Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000658 in 1,457,998 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

FAM91A1
NM_144963.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.72

Variant links:

Genes affected

FAM91A1 (HGNC:26306): (family with sequence similarity 91 member A1) Involved in intracellular protein transport and vesicle tethering to Golgi. Located in cytoplasmic vesicle and trans-Golgi network. [provided by Alliance of Genome Resources, Apr 2022]

FAM91A1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM91A1	NM_144963.4 link	c.460C>G	p.Arg154Gly	missense_variant	Exon 6 of 24	ENST00000334705.12	NP_659400.3	Q658Y4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FAM91A1	ENST00000334705.12 link	c.460C>G	p.Arg154Gly	missense_variant	Exon 6 of 24	1	NM_144963.4	ENSP00000335082.7	Q658Y4
FAM91A1	ENST00000519721.5 link	n.460C>G		non_coding_transcript_exon_variant	Exon 6 of 24	1		ENSP00000429784.1	G3V120
FAM91A1	ENST00000521166.5 link	c.460C>G	p.Arg154Gly	missense_variant	Exon 6 of 23	2		ENSP00000429491.1	E7ER68

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000201

AC:

AN:

248330

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134780

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000355

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000658

AC:

AN:

1457998

Hom.:

Cov.:

AF XY:

0.0000620

AC XY:

AN XY:

725350

show subpopulations

Gnomad4 AFR exome

AF:

0.0000600

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:

0.0000792

Gnomad4 OTH exome

AF:

0.0000999

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000901

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.460C>G (p.R154G) alteration is located in exon 6 (coding exon 6) of the FAM91A1 gene. This alteration results from a C to G substitution at nucleotide position 460, causing the arginine (R) at amino acid position 154 to be replaced by a glycine (G). 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

0.80

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

T;D

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.78

T;T

M_CAP

Benign

0.021

MetaRNN

Uncertain

0.59

D;D

MetaSVM

Benign

-0.72

MutationAssessor

Uncertain

2.5

.;M

PrimateAI

Benign

0.38

PROVEAN

Pathogenic

-4.5

D;D

REVEL

Benign

0.19

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.032

D;D

Polyphen

0.45

B;B

Vest4

0.80

MutPred

0.40

Loss of MoRF binding (P = 0.0277);Loss of MoRF binding (P = 0.0277);

MVP

0.47

MPC

1.3

ClinPred

0.91

GERP RS

5.6

Varity_R

0.50

gMVP

0.71

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over