Genetic Variant FAM170B:p.Arg245Gln (chr10-49131731-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001164484.2(FAM170B):c.734G>A(p.Arg245Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000193 in 1,551,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

FAM170B
NM_001164484.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.570

Variant links:

Genes affected

FAM170B (HGNC:19736): (family with sequence similarity 170 member B) Predicted to be involved in fertilization; positive regulation of acrosome reaction; and regulation of fertilization. Located in acrosomal vesicle. [provided by Alliance of Genome Resources, Apr 2022]

FAM170B links:

FAM170B-AS1 (HGNC:45006): (FAM170B antisense RNA 1)

FAM170B-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.019252717).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM170B	NM_001164484.2 link	c.734G>A	p.Arg245Gln	missense_variant	Exon 2 of 2	ENST00000311787.6	NP_001157956.1	A6NMN3
FAM170B-AS1	NR_038973.1 link	n.439-3925C>T		intron_variant	Intron 1 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FAM170B	ENST00000311787.6 link	c.734G>A	p.Arg245Gln	missense_variant	Exon 2 of 2	1	NM_001164484.2	ENSP00000308292.6	A6NMN3
FAM170B-AS1	ENST00000435809.1 link	n.192-4146C>T		intron_variant	Intron 1 of 2	3
FAM170B-AS1	ENST00000442525.5 link	n.439-3925C>T		intron_variant	Intron 1 of 5	2
FAM170B-AS1	ENST00000443389.5 link	n.433+9455C>T		intron_variant	Intron 1 of 5	5

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000128

AC:

AN:

156358

Hom.:

AF XY:

0.0000845

AC XY:

AN XY:

82878

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000729

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:

0.000456

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1399362

Hom.:

Cov.:

AF XY:

0.0000130

AC XY:

AN XY:

690198

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000532

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:

9.27e-7

Gnomad4 OTH exome

AF:

0.0000345

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000125

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 10, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.734G>A (p.R245Q) alteration is located in exon 2 (coding exon 2) of the FAM170B gene. This alteration results from a G to A substitution at nucleotide position 734, causing the arginine (R) at amino acid position 245 to be replaced by a glutamine (Q). 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

0.089

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.71

CADD

Benign

8.0

DANN

Benign

0.97

DEOGEN2

Benign

0.0027

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.50

M_CAP

Benign

0.0075

MetaRNN

Benign

0.019

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.66

REVEL

Benign

0.012

Sift

Benign

0.11

Sift4G

Benign

0.38

Polyphen

0.086

Vest4

0.091

MutPred

0.14

Gain of helix (P = 0.2059);

MVP

0.055

ClinPred

0.027

GERP RS

-1.6

Varity_R

0.031

gMVP

0.15

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

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