chr1-121168823-A-C

Variant names:

• chr1-121168823-A-C
• rs1654027784
• NM_001100910.2:c.368T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001100910.2(FAM72B):​c.368T>G​(p.Leu123Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L123P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FAM72B NM_001100910.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.49
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.787

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.368T>G	p.Leu123Arg	missense	Exon 4 of 4	NP_001094380.1	Q86X60-1
	FAM72B	NM_001320149.2		c.248T>G	p.Leu83Arg	missense	Exon 4 of 4	NP_001307078.1	Q86X60-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM72B	ENST00000369390.7	TSL:1 MANE Select	c.368T>G	p.Leu123Arg	missense	Exon 4 of 4	ENSP00000358397.3	Q86X60-1
	FAM72B	ENST00000355228.8	TSL:1	c.248T>G	p.Leu83Arg	missense	Exon 4 of 4	ENSP00000347368.4	Q86X60-2
	FAM72B	ENST00000619376.4	TSL:1	c.243T>G	p.Pro81Pro	synonymous	Exon 3 of 3	ENSP00000482799.1	A0A087WZP4

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1456864 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724614

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

African (AFR) AF: 0.0000301 AC: 1 AN: 33226

American (AMR) AF: 0.00 AC: 0 AN: 44150

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26030

East Asian (EAS) AF: 0.00 AC: 0 AN: 39588

South Asian (SAS) AF: 0.00 AC: 0 AN: 85352

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4124

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110924

Other (OTH) AF: 0.00 AC: 0 AN: 60094

⚠️ 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.: 25

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	26
DEOGEN2	Benign	0.11	T
LIST_S2	Uncertain	0.90	D
MetaRNN	Pathogenic	0.79	D
PhyloP100		8.5
PROVEAN	Benign	-2.2	N
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Vest4		0.92
gMVP		0.85

Splicing

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

Other links and lift over

dbSNP: rs1654027784; hg19: chr1-120854504;