10-73168341-T-G

Position:

• chr10-73168341-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_173348.2(FAM149B1):​c.2T>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000996 in 1,546,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00081 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (0 hom.)
• Consequence: FAM149B1 NM_173348.2 start_lost
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.41

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]

ECD (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM149B1	NM_173348.2	c.2T>G	p.Met1?	start_lost	1/14	ENST00000242505.11	NP_775483.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM149B1	ENST00000242505.11	c.2T>G	p.Met1?	start_lost	1/14	5	NM_173348.2	ENSP00000242505.6
ECD	ENST00000610256.1	n.178+537A>C		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.000814 AC: 122 AN: 149834 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000532

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000658

Gnomad ASJ AF: 0.000870

Gnomad EAS AF: 0.000582

Gnomad SAS AF: 0.000624

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00108

Gnomad OTH AF: 0.00194

GnomAD3 exomes AF: 0.000709 AC: 106 AN: 149474 Hom.: 0 AF XY: 0.000702 AC XY: 56 AN XY: 79782

Gnomad AFR exome AF: 0.000262

Gnomad AMR exome AF: 0.000529

Gnomad ASJ exome AF: 0.00107

Gnomad EAS exome AF: 0.000372

Gnomad SAS exome AF: 0.000836

Gnomad FIN exome AF: 0.000131

Gnomad NFE exome AF: 0.000968

Gnomad OTH exome AF: 0.000704

GnomAD4 exome AF: 0.00102 AC: 1419 AN: 1396292 Hom.: 0 Cov.: 34 AF XY: 0.00103 AC XY: 712 AN XY: 688714

Gnomad4 AFR exome AF: 0.000449

Gnomad4 AMR exome AF: 0.000618

Gnomad4 ASJ exome AF: 0.000716

Gnomad4 EAS exome AF: 0.00110

Gnomad4 SAS exome AF: 0.000682

Gnomad4 FIN exome AF: 0.000122

Gnomad4 NFE exome AF: 0.00112

Gnomad4 OTH exome AF: 0.000934

GnomAD4 genome AF: 0.000807 AC: 121 AN: 149948 Hom.: 0 Cov.: 32 AF XY: 0.000873 AC XY: 64 AN XY: 73326

Gnomad4 AFR AF: 0.000530

Gnomad4 AMR AF: 0.000658

Gnomad4 ASJ AF: 0.000870

Gnomad4 EAS AF: 0.000583

Gnomad4 SAS AF: 0.000625

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.00106

Gnomad4 OTH AF: 0.00192

Alfa AF: 0.000793 Hom.: 0

Bravo AF: 0.000710

ExAC AF: 0.000315 AC: 13

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 08, 2024

Variant summary: FAM149B1 c.2T>G (p.Met1Arg) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. However, loss-of-function has yet to be established as a mechanism of disease. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.001 in 1546240 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in FAM149B1 causing Joubert Syndrome 36, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.2T>G in individuals affected with Joubert Syndrome 36 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 3148839). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Joubert syndrome 36 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.060	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-1.1	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.80
MVP		0.14
ClinPred		0.13	T
GERP RS		4.9
Varity_R		0.97
gMVP		0.67

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

Other links and lift over

dbSNP: rs569932117; hg19: chr10-74928099; COSMIC: COSV54354157; COSMIC: COSV54354157;