Genetic Variant FAM185A:p.Lys187Glu (chr7-102751799-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001145268.2(FAM185A):c.559A>G(p.Lys187Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000197 in 1,522,824 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 29)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

FAM185A
NM_001145268.2 missense, splice_region

Scores

Splicing: ADA: 0.3236

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.58

Publications

0 publications found

Variant links:

Genes affected

FAM185A (HGNC:22412): (family with sequence similarity 185 member A)

FAM185A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM185A	NM_001145268.2 link	c.559A>G	p.Lys187Glu	missense_variant, splice_region_variant	Exon 2 of 8	ENST00000413034.3	NP_001138740.2	Q8N0U4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM185A	ENST00000413034.3 link	c.559A>G	p.Lys187Glu	missense_variant, splice_region_variant	Exon 2 of 8	5	NM_001145268.2	ENSP00000395340.2		Q8N0U4-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152042

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

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

GnomAD2 exomes

AF:

0.0000147

AC:

AN:

136432

AF XY:

0.0000139

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000527

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000182

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000146

AC:

AN:

1370782

Hom.:

Cov.:

AF XY:

0.00000148

AC XY:

AN XY:

675874

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29902

American (AMR)

AF:

0.0000335

AC:

AN:

29860

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24168

East Asian (EAS)

AF:

0.00

AC:

AN:

34832

South Asian (SAS)

AF:

0.00

AC:

AN:

74058

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48752

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5556

European-Non Finnish (NFE)

AF:

9.37e-7

AC:

AN:

1066968

Other (OTH)

AF:

0.00

AC:

AN:

56686

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152042

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41386

American (AMR)

AF:

0.0000656

AC:

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 29, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.559A>G (p.K187E) alteration is located in exon 2 (coding exon 2) of the FAM185A gene. This alteration results from a A to G substitution at nucleotide position 559, causing the lysine (K) at amino acid position 187 to be replaced by a glutamic acid (E). 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

0.81

BayesDel_addAF

Benign

-0.082

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

.;T

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.76

T;T

M_CAP

Benign

0.049

MetaRNN

Uncertain

0.63

D;D

MetaSVM

Benign

-0.58

MutationAssessor

Uncertain

2.8

.;M

PhyloP100

6.6

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.3

D;D

REVEL

Uncertain

0.32

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.95

.;P

Vest4

0.51

MutPred

0.60

Loss of MoRF binding (P = 0.011);Loss of MoRF binding (P = 0.011);

MVP

0.16

ClinPred

0.87

GERP RS

4.0

Varity_R

0.31

gMVP

0.63

Mutation Taster

=44/56

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.32

dbscSNV1_RF

Benign

0.40

SpliceAI score (max)

0.010

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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7-102751799-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over