Genetic Variant FAM171A2:p.Thr568Arg (chr17-44354511-G-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_198475.3(FAM171A2):c.1703C>G(p.Thr568Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000615 in 975,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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: 0.0000061 ( 0 hom. )

Consequence

FAM171A2
NM_198475.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.51

Publications

0 publications found

Variant links:

Genes affected

FAM171A2 (HGNC:30480): (family with sequence similarity 171 member A2) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

FAM171A2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06726718).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM171A2	NM_198475.3 link	c.1703C>G	p.Thr568Arg	missense_variant	Exon 8 of 8	ENST00000293443.12	NP_940877.2	A8MVW0
FAM171A2	XM_017024490.2 link	c.1151C>G	p.Thr384Arg	missense_variant	Exon 6 of 6		XP_016879979.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM171A2	ENST00000293443.12 link	c.1703C>G	p.Thr568Arg	missense_variant	Exon 8 of 8	1	NM_198475.3	ENSP00000293443.6		A8MVW0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000615

AC:

AN:

975634

Hom.:

Cov.:

AF XY:

0.00000436

AC XY:

AN XY:

459214

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

19328

American (AMR)

AF:

0.00

AC:

AN:

5234

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9542

East Asian (EAS)

AF:

0.00

AC:

AN:

16126

South Asian (SAS)

AF:

0.000323

AC:

AN:

18568

European-Finnish (FIN)

AF:

0.00

AC:

AN:

16208

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2354

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

852004

Other (OTH)

AF:

0.00

AC:

AN:

36270

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 16, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1703C>G (p.T568R) alteration is located in exon 8 (coding exon 8) of the FAM171A2 gene. This alteration results from a C to G substitution at nucleotide position 1703, causing the threonine (T) at amino acid position 568 to be replaced by an arginine (R). 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

0.14

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.0039

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.33

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.067

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

PhyloP100

1.5

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-1.0

REVEL

Benign

0.091

Sift

Benign

0.41

Sift4G

Benign

0.45

Polyphen

0.0040

Vest4

0.077

MutPred

0.35

Loss of glycosylation at T568 (P = 0.0046);

MVP

0.030

ClinPred

0.086

GERP RS

3.5

Varity_R

0.14

gMVP

0.27

Mutation Taster

=95/5

polymorphism

(source)

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

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17-44354511-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over