8-123787318-C-T

Variant names:

• chr8-123787318-C-T
• rs1434511935
• NM_144963.4:c.1136C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_144963.4(FAM91A1):​c.1136C>T​(p.Ala379Val) variant causes a missense change involving the alteration of a conserved nucleotide. 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FAM91A1 NM_144963.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.85

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.84

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM91A1	NM_144963.4	c.1136C>T	p.Ala379Val	missense_variant	Exon 13 of 24	ENST00000334705.12	NP_659400.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM91A1	ENST00000334705.12	c.1136C>T	p.Ala379Val	missense_variant	Exon 13 of 24	1	NM_144963.4	ENSP00000335082.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1136C>T (p.A379V) alteration is located in exon 13 (coding exon 13) of the FAM91A1 gene. This alteration results from a C to T substitution at nucleotide position 1136, causing the alanine (A) at amino acid position 379 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	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.087	T;T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Benign	-0.45	T
MutationAssessor	Uncertain	2.7	.;M
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		1.0	D;D
Vest4		0.94
MutPred		0.43		Loss of disorder (P = 0.0932);Loss of disorder (P = 0.0932);
MVP		0.52
MPC		1.1
ClinPred		0.95	D
GERP RS		5.7
Varity_R		0.41
gMVP		0.81

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: rs1434511935; hg19: chr8-124799558;