Genetic Variant FAM180A:p.Arg105Cys (chr7-135734184-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_205855.4(FAM180A):c.313C>T(p.Arg105Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000223 in 1,614,068 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

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

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

FAM180A
NM_205855.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.79

Variant links:

Genes affected

FAM180A (HGNC:33773): (family with sequence similarity 180 member A) Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

FAM180A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.801

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM180A	NM_205855.4 link	c.313C>T	p.Arg105Cys	missense_variant	Exon 3 of 4	ENST00000338588.8	NP_995327.1	Q6UWF9
FAM180A	NM_001369697.2 link	c.313C>T	p.Arg105Cys	missense_variant	Exon 3 of 3		NP_001356626.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FAM180A	ENST00000338588.8 link	c.313C>T	p.Arg105Cys	missense_variant	Exon 3 of 4	1	NM_205855.4	ENSP00000342336.3	Q6UWF9
FAM180A	ENST00000444083.5 link	n.313C>T		non_coding_transcript_exon_variant	Exon 3 of 4	1		ENSP00000406553.1	Q6UWF9
FAM180A	ENST00000435869.1 link	n.410+2915C>T		intron_variant	Intron 2 of 2	1
FAM180A	ENST00000415751.1 link	c.313C>T	p.Arg105Cys	missense_variant	Exon 3 of 3	2		ENSP00000395467.1	Q6UWF9

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251432

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

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:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000198

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.313C>T (p.R105C) alteration is located in exon 3 (coding exon 3) of the FAM180A gene. This alteration results from a C to T substitution at nucleotide position 313, causing the arginine (R) at amino acid position 105 to be replaced by a cysteine (C). 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

0.26

BayesDel_addAF

Uncertain

0.017

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.12

T;T

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

D;.

M_CAP

Benign

0.062

MetaRNN

Pathogenic

0.80

D;D

MetaSVM

Benign

-0.67

MutationAssessor

Uncertain

2.6

M;M

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-5.5

D;D

REVEL

Benign

0.23

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.0080

D;D

Polyphen

1.0

D;D

Vest4

0.81

MutPred

0.31

Loss of disorder (P = 0.0162);Loss of disorder (P = 0.0162);

MVP

0.32

MPC

0.60

ClinPred

0.98

GERP RS

5.3

Varity_R

0.45

gMVP

0.56

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