15-59508923-A-T

Position:

• chr15-59508923-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_152450.3(FAM81A):​c.604A>T​(p.Met202Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: FAM81A NM_152450.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.896

Genes affected

FAM81A (HGNC:28379): (family with sequence similarity 81 member A)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.040334016).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM81A	NM_152450.3	c.604A>T	p.Met202Leu	missense_variant	6/9	ENST00000288228.10	NP_689663.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM81A	ENST00000288228.10	c.604A>T	p.Met202Leu	missense_variant	6/9	1	NM_152450.3	ENSP00000288228.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000201 AC: 5 AN: 249086 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135124

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

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: 0.00000342 AC: 5 AN: 1461112 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726838

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000166 AC: 2

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

Jul 25, 2023

The c.604A>T (p.M202L) alteration is located in exon 6 (coding exon 5) of the FAM81A gene. This alteration results from a A to T substitution at nucleotide position 604, causing the methionine (M) at amino acid position 202 to be replaced by a leucine (L). 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	0.13
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Benign	0.90
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.22
Eigen_PC	Benign	0.00015
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.11
Sift	Benign	0.61	T
Sift4G	Benign	0.34	T
Polyphen		0.0010	B
Vest4		0.16
MutPred		0.094		Loss of MoRF binding (P = 0.115);
MVP		0.040
MPC		0.42
ClinPred		0.067	T
GERP RS		5.7
Varity_R		0.15
gMVP		0.10

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs758247940; hg19: chr15-59801122;