chr15-92655357-A-C

Position:

• chr15-92655357-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000327355.6(FAM174B):​c.303T>G​(p.Phe101Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000627 in 1,436,550 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000063 (0 hom.)
• Consequence: FAM174B ENST00000327355.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.76

Genes affected

FAM174B (HGNC:34339): (family with sequence similarity 174 member B) Involved in Golgi organization. Located in Golgi apparatus and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

FAM174B (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10485798).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM174B	NM_207446.3	c.303T>G	p.Phe101Leu	missense_variant	1/3	ENST00000327355.6	NP_997329.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM174B	ENST00000327355.6	c.303T>G	p.Phe101Leu	missense_variant	1/3	1	NM_207446.3	ENSP00000329040.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000627 AC: 9 AN: 1436550 Hom.: 0 Cov.: 31 AF XY: 0.00000979 AC XY: 7 AN XY: 714772

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: 0.00000727

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000468 Hom.: 0

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

Apr 08, 2024

The c.303T>G (p.F101L) alteration is located in exon 1 (coding exon 1) of the FAM174B gene. This alteration results from a T to G substitution at nucleotide position 303, causing the phenylalanine (F) at amino acid position 101 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	Pathogenic	0.67
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Benign	0.0064	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.075
Sift	Benign	0.67	T
Sift4G	Benign	1.0	T
Polyphen		0.049	B
Vest4		0.25
MutPred		0.58		Loss of MoRF binding (P = 0.1919);
MVP		0.014
MPC		0.44
ClinPred		0.41	T
GERP RS		3.1
Varity_R		0.11
gMVP		0.34

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: rs1331889594; hg19: chr15-93198587;