8-123798101-G-A

Variant names:

• chr8-123798101-G-A
• rs760860540
• NM_144963.4:c.1423G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_144963.4(FAM91A1):​c.1423G>A​(p.Asp475Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,102 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FAM91A1 NM_144963.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.73

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.859

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM91A1	NM_144963.4	c.1423G>A	p.Asp475Asn	missense_variant	Exon 16 of 24	ENST00000334705.12	NP_659400.3
FAM91A1	NM_001317918.1	c.1423G>A	p.Asp475Asn	missense_variant	Exon 16 of 23		NP_001304847.1
FAM91A1	NM_001317917.2	c.697G>A	p.Asp233Asn	missense_variant	Exon 16 of 24		NP_001304846.2
FAM91A1	XM_047421405.1	c.1198G>A	p.Asp400Asn	missense_variant	Exon 17 of 25		XP_047277361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM91A1	ENST00000334705.12	c.1423G>A	p.Asp475Asn	missense_variant	Exon 16 of 24	1	NM_144963.4	ENSP00000335082.7
FAM91A1	ENST00000519721.5	n.*773G>A		non_coding_transcript_exon_variant	Exon 16 of 24	1		ENSP00000429784.1
FAM91A1	ENST00000519721.5	n.*773G>A		3_prime_UTR_variant	Exon 16 of 24	1		ENSP00000429784.1
FAM91A1	ENST00000521166.5	c.1423G>A	p.Asp475Asn	missense_variant	Exon 16 of 23	2		ENSP00000429491.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 248010 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134584

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000293

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460102 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726360

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: 9.00e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 04, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1423G>A (p.D475N) alteration is located in exon 16 (coding exon 16) of the FAM91A1 gene. This alteration results from a G to A substitution at nucleotide position 1423, causing the aspartic acid (D) at amino acid position 475 to be replaced by an asparagine (N). 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	0.99
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.13	T;T
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.6	.;M
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.56		Gain of catalytic residue at D475 (P = 0.0401);Gain of catalytic residue at D475 (P = 0.0401);
MVP		0.78
MPC		1.3
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.85
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.28		Position offset: 20

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs760860540; hg19: chr8-124810341;