dbSNP rs1184323456: FAM78B:p.Met246Ile (chr1-166070289-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001017961.5(FAM78B):c.738G>T(p.Met246Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000705 in 1,418,292 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

FAM78B
NM_001017961.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.80

Publications

0 publications found

Variant links:

Genes affected

FAM78B (HGNC:13495): (family with sequence similarity 78 member B)

FAM78B links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001017961.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAM78B	NM_001017961.5	MANE Select	c.738G>T	p.Met246Ile	missense	Exon 2 of 2	NP_001017961.1	Q5VT40
FAM78B	NM_001320302.2		c.264-9626G>T		intron	N/A	NP_001307231.1	F1T0K0
FAM78B	NR_135199.2		n.1491G>T		non_coding_transcript_exon	Exon 2 of 3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAM78B	ENST00000354422.4	TSL:2 MANE Select	c.738G>T	p.Met246Ile	missense	Exon 2 of 2	ENSP00000346404.3	Q5VT40
FAM78B	ENST00000338353.4	TSL:1	c.738G>T	p.Met246Ile	missense	Exon 3 of 3	ENSP00000339681.3	Q5VT40
FAM78B	ENST00000435676.2	TSL:2	n.714G>T		non_coding_transcript_exon	Exon 2 of 3	ENSP00000412766.1	H7C3M6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.05e-7

AC:

AN:

1418292

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

699626

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

32650

American (AMR)

AF:

0.00

AC:

AN:

41048

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22758

East Asian (EAS)

AF:

0.0000255

AC:

AN:

39274

South Asian (SAS)

AF:

0.00

AC:

AN:

78360

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5534

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1088476

Other (OTH)

AF:

0.00

AC:

AN:

58582

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.040

Eigen

Uncertain

0.62

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.88

M_CAP

Uncertain

0.090

MetaRNN

Uncertain

0.69

MetaSVM

Uncertain

0.49

MutationAssessor

Benign

1.6

PhyloP100

7.8

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.56

REVEL

Uncertain

0.60

Sift

Benign

0.72

Sift4G

Benign

0.31

Polyphen

0.91

Vest4

0.80

MutPred

0.37

Gain of sheet (P = 0.0477)

MVP

0.99

MPC

1.7

ClinPred

0.93

GERP RS

6.0

Varity_R

0.24

gMVP

0.36

Mutation Taster

=33/67

disease causing

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over