8-123789661-C-T

Variant names:

• chr8-123789661-C-T
• rs1815336178
• NM_144963.4:c.1327C>T

Variant summary

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

The NM_144963.4(FAM91A1):​c.1327C>T​(p.Leu443Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 4.52

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 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	c.1327C>T	p.Leu443Phe	missense_variant	Exon 15 of 24	ENST00000334705.12	NP_659400.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM91A1	ENST00000334705.12	c.1327C>T	p.Leu443Phe	missense_variant	Exon 15 of 24	1	NM_144963.4	ENSP00000335082.7
FAM91A1	ENST00000519721.5	n.*677C>T		non_coding_transcript_exon_variant	Exon 15 of 24	1		ENSP00000429784.1
FAM91A1	ENST00000519721.5	n.*677C>T		3_prime_UTR_variant	Exon 15 of 24	1		ENSP00000429784.1
FAM91A1	ENST00000521166.5	c.1327C>T	p.Leu443Phe	missense_variant	Exon 15 of 23	2		ENSP00000429491.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Dec 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1327C>T (p.L443F) alteration is located in exon 15 (coding exon 15) of the FAM91A1 gene. This alteration results from a C to T substitution at nucleotide position 1327, causing the leucine (L) at amino acid position 443 to be replaced by a phenylalanine (F). 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	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.040	T;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	.;L
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.5	D;D
REVEL	Benign	0.24
Sift	Benign	0.050	D;D
Sift4G	Benign	0.083	T;T
Polyphen		0.98	D;D
Vest4		0.81
MutPred		0.28		Loss of catalytic residue at L443 (P = 0.0869);Loss of catalytic residue at L443 (P = 0.0869);
MVP		0.34
MPC		0.64
ClinPred		0.94	D
GERP RS		5.2
Varity_R		0.43
gMVP		0.43

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: rs1815336178; hg19: chr8-124801901;