chr10-73193566-C-A

Variant names:

Variant summary

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

The NM_173348.2(FAM149B1):c.515C>A(p.Thr172Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000232 in 1,550,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T172I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

FAM149B1
NM_173348.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.137

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:

Genome browser will be placed here

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=0.041881293).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM149B1	NM_173348.2 link	c.515C>A	p.Thr172Asn	missense_variant	Exon 5 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.515C>A	p.Thr172Asn	missense_variant	Exon 5 of 14	5	NM_173348.2	ENSP00000242505.6	Q96BN6-1
FAM149B1	ENST00000372955.7 link	c.335C>A	p.Thr112Asn	missense_variant	Exon 3 of 10	1		ENSP00000362046.3	H7BY93
DNAJC9	ENST00000469143.1 link	n.148-9990G>T		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000256

AC:

AN:

156304

AF XY:

0.0000362

show subpopulations

Gnomad AFR exome

AF:

0.000126

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000165

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000186

AC:

AN:

1398582

Hom.:

Cov.:

AF XY:

0.0000174

AC XY:

AN XY:

689846

show subpopulations

African (AFR)

AF:

0.000475

AC:

AN:

31580

American (AMR)

AF:

0.0000280

AC:

AN:

35688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25168

East Asian (EAS)

AF:

0.00

AC:

AN:

35646

South Asian (SAS)

AF:

0.0000379

AC:

AN:

79204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49162

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5672

European-Non Finnish (NFE)

AF:

0.00000371

AC:

AN:

1078490

Other (OTH)

AF:

0.0000517

AC:

AN:

57972

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41536

American (AMR)

AF:

0.000131

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000131

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000411

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 16, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.515C>A (p.T172N) alteration is located in exon 5 (coding exon 5) of the FAM149B1 gene. This alteration results from a C to A substitution at nucleotide position 515, causing the threonine (T) at amino acid position 172 to be replaced by an asparagine (N). 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

0.082

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.64

CADD

Benign

7.4

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.0015

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.66

M_CAP

Benign

0.0066

MetaRNN

Benign

0.042

MetaSVM

Benign

-1.1

PhyloP100

-0.14

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.31

REVEL

Benign

0.0030

Sift

Benign

0.23

Sift4G

Benign

0.14

Polyphen

0.0020

Vest4

0.081

MVP

0.014

ClinPred

0.0059

GERP RS

-2.2

Varity_R

0.046

gMVP

0.22

Mutation Taster

=92/8

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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chr10-73193566-C-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