1-121177263-G-T

Variant names:

• chr1-121177263-G-T
• rs1654233724
• NM_001100910.2:c.300C>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001100910.2(FAM72B):​c.300C>A​(p.His100Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H100N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 20)
• Consequence: FAM72B NM_001100910.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.52

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.846

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM72B	NM_001100910.2	c.300C>A	p.His100Gln	missense_variant	Exon 3 of 4	ENST00000369390.7	NP_001094380.1
FAM72B	NM_001320149.2	c.180C>A	p.His60Gln	missense_variant	Exon 3 of 4		NP_001307078.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM72B	ENST00000369390.7	c.300C>A	p.His100Gln	missense_variant	Exon 3 of 4	1	NM_001100910.2	ENSP00000358397.3

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 20

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 17, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.300C>A (p.H100Q) alteration is located in exon 3 (coding exon 3) of the FAM72B gene. This alteration results from a C to A substitution at nucleotide position 300, causing the histidine (H) at amino acid position 100 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	22
DEOGEN2	Benign	0.29	T;.;.;.
Eigen	Benign	-0.0015
Eigen_PC	Benign	0.086
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Benign	-1.0	T
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-6.5	D;D;.;D
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Benign	0.085	T;T;T;T
Vest4		0.95
MutPred		0.67		Gain of sheet (P = 0.1208);.;Gain of sheet (P = 0.1208);.;
MVP		0.23
ClinPred		0.95	D
GERP RS		3.4
Varity_R		0.80
gMVP		0.79

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1654233724; hg19: chr1-143906067;