X-55146214-G-A

Position:

• chrX-55146214-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001166701.4(FAM104B):​c.218C>T​(p.Pro73Leu) 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 benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: FAM104B NM_001166701.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.840

Genes affected

FAM104B (HGNC:25085): (VCP nuclear cofactor family member 2)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.054038584).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM104B	NM_001166701.4	c.218C>T	p.Pro73Leu	missense_variant	3/3	ENST00000685693.1	NP_001160173.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM104B	ENST00000685693.1	c.218C>T	p.Pro73Leu	missense_variant	3/3		NM_001166701.4	ENSP00000509111	A2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.221C>T (p.P74L) alteration is located in exon 3 (coding exon 3) of the FAM104B gene. This alteration results from a C to T substitution at nucleotide position 221, causing the proline (P) at amino acid position 74 to be replaced by a leucine (L). 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	Benign	0.093
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.3
DANN	Benign	0.78
DEOGEN2	Benign	0.014	.;T;.;.;.
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.71	T;T;T;T;T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.054	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	.;L;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.45	N;N;N;N;N
REVEL	Benign	0.035
Sift	Benign	0.32	T;T;T;T;T
Sift4G	Benign	0.12	T;D;T;T;T
Polyphen		0.94	P;P;B;.;.
Vest4		0.14
MutPred		0.34		.;Gain of sheet (P = 0.0266);.;.;.;
MVP		0.092
MPC		0.46
ClinPred		0.058	T
GERP RS		-0.40
Varity_R		0.041
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs866839768; hg19: chrX-55172647; COSMIC: COSV100146088; COSMIC: COSV100146088;