Genetic Variant FAM149B1:p.Glu117Lys (chr10-73192622-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_173348.2(FAM149B1):c.349G>A(p.Glu117Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000715 in 1,399,496 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: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

FAM149B1
NM_173348.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.89

Publications

0 publications found

Variant links:

Genes affected

FAM149B1 (HGNC:29162): (family with sequence similarity 149 member B1) Involved in cilium assembly and protein localization to cilium. Predicted to be located in cilium. Implicated in Joubert syndrome. [provided by Alliance of Genome Resources, Apr 2022]

FAM149B1 links:

DNAJC9 (HGNC:19123): (DnaJ heat shock protein family (Hsp40) member C9) Enables chaperone binding activity; heat shock protein binding activity; and histone binding activity. Involved in nucleosome assembly and positive regulation of ATPase activity. Located in several cellular components, including cytosol; extracellular space; and nucleoplasm. Part of chaperone complex. [provided by Alliance of Genome Resources, Apr 2022]

DNAJC9 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.781

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM149B1	NM_173348.2 link	c.349G>A	p.Glu117Lys	missense_variant	Exon 4 of 14	ENST00000242505.11	NP_775483.1	Q96BN6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FAM149B1	ENST00000242505.11 link	c.349G>A	p.Glu117Lys	missense_variant	Exon 4 of 14	5	NM_173348.2	ENSP00000242505.6	Q96BN6-1
FAM149B1	ENST00000372955.7 link	c.169G>A	p.Glu57Lys	missense_variant	Exon 2 of 10	1		ENSP00000362046.3	H7BY93
DNAJC9	ENST00000469143.1 link	n.148-9046C>T		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.15e-7

AC:

AN:

1399496

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

690248

show subpopulations

African (AFR)

AF:

0.0000317

AC:

AN:

31586

American (AMR)

AF:

0.00

AC:

AN:

35574

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25178

East Asian (EAS)

AF:

0.00

AC:

AN:

35702

South Asian (SAS)

AF:

0.00

AC:

AN:

79148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49546

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078914

Other (OTH)

AF:

0.00

AC:

AN:

58148

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 18, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.349G>A (p.E117K) alteration is located in exon 4 (coding exon 4) of the FAM149B1 gene. This alteration results from a G to A substitution at nucleotide position 349, causing the glutamic acid (E) at amino acid position 117 to be replaced by a lysine (K). 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

0.27

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.24

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.048

MetaRNN

Pathogenic

0.78

MetaSVM

Uncertain

-0.20

MutationAssessor

Pathogenic

3.2

PhyloP100

6.9

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.6

REVEL

Uncertain

0.43

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.74

MutPred

0.51

Gain of methylation at E117 (P = 0.0214);

MVP

0.21

ClinPred

1.0

GERP RS

5.5

Varity_R

0.88

gMVP

0.76

Mutation Taster

=70/30

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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10-73192622-G-A

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