Genetic Variant FAM72B:p.Met30Lys (chr1-121183401-A-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_001100910.2(FAM72B):c.89T>A(p.Met30Lys) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 10/15 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., cov: 13)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FAM72B
NM_001100910.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.24

Publications

1 publications found

Variant links:

Genes affected

FAM72B (HGNC:24805): (family with sequence similarity 72 member B) Located in cytosol and intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

FAM72B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PP3

MetaRNN computational evidence supports a deleterious effect, 0.848

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001100910.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM72B	NM_001100910.2	MANE Select	c.89T>A	p.Met30Lys	missense	Exon 1 of 4	NP_001094380.1	Q86X60-1
	FAM72B	NM_001320149.2		c.32+57T>A		intron	N/A	NP_001307078.1	Q86X60-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAM72B	ENST00000369390.7	TSL:1 MANE Select	c.89T>A	p.Met30Lys	missense	Exon 1 of 4	ENSP00000358397.3	Q86X60-1
FAM72B	ENST00000619376.4	TSL:1	c.89T>A	p.Met30Lys	missense	Exon 1 of 3	ENSP00000482799.1	A0A087WZP4
FAM72B	ENST00000355228.8	TSL:1	c.32+57T>A		intron	N/A	ENSP00000347368.4	Q86X60-2

Frequencies

GnomAD3 genomes

AF:

0.00000900

AC:

AN:

111064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000728

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000282

AC:

AN:

1419120

Hom.:

Cov.:

AF XY:

0.00000284

AC XY:

AN XY:

704372

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32052

American (AMR)

AF:

0.0000240

AC:

AN:

41622

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24972

East Asian (EAS)

AF:

0.00

AC:

AN:

39256

South Asian (SAS)

AF:

0.0000359

AC:

AN:

83666

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52784

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3982

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1082312

Other (OTH)

AF:

0.00

AC:

AN:

58474

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.412

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000900

AC:

AN:

111064

Hom.:

Cov.:

AF XY:

0.0000191

AC XY:

AN XY:

52338

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

27690

American (AMR)

AF:

0.00

AC:

AN:

10130

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2942

East Asian (EAS)

AF:

0.00

AC:

AN:

3672

South Asian (SAS)

AF:

0.00

AC:

AN:

2634

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

270

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

55136

Other (OTH)

AF:

0.000728

AC:

AN:

1374

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

(source)

DEOGEN2

Benign

0.20

Eigen

Pathogenic

0.68

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.076

MetaRNN

Pathogenic

0.84

MetaSVM

Benign

-0.69

PhyloP100

8.2

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-4.9

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.86

MutPred

0.59

Loss of stability (P = 0.0212)

MVP

0.54

ClinPred

0.99

GERP RS

3.8

gMVP

0.66

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over