1-166070289-C-A

Variant names:

• chr1-166070289-C-A
• rs1184323456
• NM_001017961.5:c.738G>T

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.80
• Publications: 0 publications found

Genes affected

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

ACMG classification

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

Sel.	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

Sel.	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.: 32

GnomAD4 exome AF: 7.05e-7 AC: 1 AN: 1418292 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 699626

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

African (AFR) AF: 0.00 AC: 0 AN: 32650

American (AMR) AF: 0.00 AC: 0 AN: 41048

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22758

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39274

South Asian (SAS) AF: 0.00 AC: 0 AN: 78360

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5534

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1088476

Other (OTH) AF: 0.00 AC: 0 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.

GnomAD4 genome Cov.: 32

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	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.040	T
Eigen	Uncertain	0.62
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.090	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Benign	1.6	L
PhyloP100		7.8
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.56	N
REVEL	Uncertain	0.60
Sift	Benign	0.72	T
Sift4G	Benign	0.31	T
Polyphen		0.91	P
Vest4		0.80
MutPred		0.37		Gain of sheet (P = 0.0477)
MVP		0.99
MPC		1.7
ClinPred		0.93	D
GERP RS		6.0
Varity_R		0.24
gMVP		0.36
Mutation Taster		=33/67	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: rs1184323456; hg19: chr1-166039526;