10-73168341-T-G

Variant names:

• chr10-73168341-T-G
• rs569932117
• NM_173348.2:c.2T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PVS1_Supporting BS1_Supporting

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
• Publications: 3 publications found

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:17029): (ecdysoneless cell cycle regulator) Enables histone acetyltransferase binding activity. Involved in positive regulation of transcription by RNA polymerase II. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 107 codons. Genomic position: 73192592. Lost 0.182 part of the original CDS.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000807 (121/149948) while in subpopulation NFE AF = 0.00106 (72/67876). AF 95% confidence interval is 0.000864. There are 0 homozygotes in GnomAd4. There are 64 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM149B1	NM_173348.2	c.2T>G	p.Met1?	start_lost	Exon 1 of 14	ENST00000242505.11	NP_775483.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM149B1	ENST00000242505.11	c.2T>G	p.Met1?	start_lost	Exon 1 of 14	5	NM_173348.2	ENSP00000242505.6
ECD	ENST00000610256.1	n.178+537A>C		intron_variant	Intron 1 of 3	5
ECD	ENST00000453402.5	c.-493A>C		upstream_gene_variant		2		ENSP00000391367.1

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

GnomAD2 exomes AF: 0.000709 AC: 106 AN: 149474 AF XY: 0.000702

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000449 AC: 14 AN: 31148

American (AMR) AF: 0.000618 AC: 22 AN: 35626

Ashkenazi Jewish (ASJ) AF: 0.000716 AC: 18 AN: 25132

East Asian (EAS) AF: 0.00110 AC: 39 AN: 35616

South Asian (SAS) AF: 0.000682 AC: 54 AN: 79130

European-Finnish (FIN) AF: 0.000122 AC: 6 AN: 49160

Middle Eastern (MID) AF: 0.000218 AC: 1 AN: 4588

European-Non Finnish (NFE) AF: 0.00112 AC: 1211 AN: 1078068

Other (OTH) AF: 0.000934 AC: 54 AN: 57824

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.000530 AC: 21 AN: 39594

American (AMR) AF: 0.000658 AC: 10 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.000870 AC: 3 AN: 3450

East Asian (EAS) AF: 0.000583 AC: 3 AN: 5144

South Asian (SAS) AF: 0.000625 AC: 3 AN: 4802

European-Finnish (FIN) AF: 0.000472 AC: 5 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00106 AC: 72 AN: 67876

Other (OTH) AF: 0.00192 AC: 4 AN: 2086

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

Jul 08, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
PhyloP100		3.4
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
PromoterAI		-0.041	Neutral
Varity_R		0.97
gMVP		0.67
Mutation Taster		=43/157	disease causing

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

Other links and lift over

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