Genetic Variant FAM171B:p.Ile158Thr (chr2-186743483-T-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_177454.4(FAM171B):c.473T>C(p.Ile158Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000206 in 1,598,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

FAM171B
NM_177454.4 missense, splice_region

Scores

Splicing: ADA: 0.8703

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.91

Variant links:

Genes affected

FAM171B (HGNC:29412): (family with sequence similarity 171 member B) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

FAM171B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, 0.845

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM171B	NM_177454.4 link	c.473T>C	p.Ile158Thr	missense_variant, splice_region_variant	Exon 3 of 8	ENST00000304698.10	NP_803237.3	Q6P995-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM171B	ENST00000304698.10 link	c.473T>C	p.Ile158Thr	missense_variant, splice_region_variant	Exon 3 of 8	1	NM_177454.4	ENSP00000304108.5		Q6P995-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000240

AC:

AN:

250454

Hom.:

AF XY:

0.0000443

AC XY:

AN XY:

135352

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000988

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000221

AC:

AN:

1446290

Hom.:

Cov.:

AF XY:

0.0000333

AC XY:

AN XY:

720648

show subpopulations

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:

0.000163

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000910

Gnomad4 OTH exome

AF:

0.000100

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152304

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.473T>C (p.I158T) alteration is located in exon 3 (coding exon 3) of the FAM171B gene. This alteration results from a T to C substitution at nucleotide position 473, causing the isoleucine (I) at amino acid position 158 to be replaced by a threonine (T). 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

0.80

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

T;.

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.026

MetaRNN

Pathogenic

0.84

D;D

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.9

L;.

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-2.7

D;.

REVEL

Uncertain

0.42

Sift

Uncertain

0.0060

D;.

Sift4G

Uncertain

0.010

D;D

Polyphen

1.0

D;.

Vest4

0.89

MutPred

0.77

Gain of disorder (P = 0.0202);Gain of disorder (P = 0.0202);

MVP

0.67

MPC

1.1

ClinPred

0.88

GERP RS

6.0

Varity_R

0.29

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.87

dbscSNV1_RF

Benign

0.70

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over