1-222750015-A-T

Position:

• chr1-222750015-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001394345.1(FAM177B):​c.434A>T​(p.Tyr145Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,722 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: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: FAM177B NM_001394345.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.66

Genes affected

FAM177B (HGNC:34395): (family with sequence similarity 177 member B)

FAM177B (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30244994).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM177B	NM_001394345.1	c.434A>T	p.Tyr145Phe	missense_variant	6/6	ENST00000445590.4	NP_001381274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM177B	ENST00000445590.4	c.434A>T	p.Tyr145Phe	missense_variant	6/6	5	NM_001394345.1	ENSP00000414451.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461722 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727174

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Jun 29, 2023

The c.434A>T (p.Y145F) alteration is located in exon 6 (coding exon 4) of the FAM177B gene. This alteration results from a A to T substitution at nucleotide position 434, causing the tyrosine (Y) at amino acid position 145 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	Benign	0.17
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.027	T;T
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.61	.;T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.18
Sift	Uncertain	0.028	D;D
Sift4G	Benign	0.068	T;T
Polyphen		1.0	D;D
Vest4		0.49
MutPred		0.37		Loss of phosphorylation at Y145 (P = 0.0302);Loss of phosphorylation at Y145 (P = 0.0302);
MVP		0.030
MPC		0.65
ClinPred		0.82	D
GERP RS		4.0
Varity_R		0.19
gMVP		0.11

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: rs1658985114; hg19: chr1-222923357;