X-55159157-G-A

Position:

• chrX-55159157-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001166701.4(FAM104B):​c.92C>T​(p.Pro31Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000101 in 1,092,858 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 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)
  • Exomes 𝑓: 0.000010 (0 hom. 3 hem.)
• Consequence: FAM104B NM_001166701.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0180

Genes affected

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

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08290717).
• BS2: High Hemizygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM104B	NM_001166701.4	c.92C>T	p.Pro31Leu	missense_variant	2/3	ENST00000685693.1	NP_001160173.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM104B	ENST00000685693.1	c.92C>T	p.Pro31Leu	missense_variant	2/3		NM_001166701.4	ENSP00000509111	A2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000114 AC: 2 AN: 176131 Hom.: 0 AF XY: 0.0000163 AC XY: 1 AN XY: 61203

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000387

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000126

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000101 AC: 11 AN: 1092858 Hom.: 0 Cov.: 29 AF XY: 0.00000836 AC XY: 3 AN XY: 358962

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000577

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000107

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.0000151

ExAC AF: 0.0000247 AC: 3

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

May 14, 2024

The c.92C>T (p.P31L) alteration is located in exon 2 (coding exon 2) of the FAM104B gene. This alteration results from a C to T substitution at nucleotide position 92, causing the proline (P) at amino acid position 31 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	0.12
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	7.3
DANN	Benign	0.94
DEOGEN2	Benign	0.062	.;T;.;.;.;.
FATHMM_MKL	Benign	0.0082	N
LIST_S2	Uncertain	0.89	D;D;D;D;D;D
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.083	T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.3	L;L;L;L;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-6.5	D;D;D;D;D;D
REVEL	Benign	0.032
Sift	Benign	0.044	D;T;T;D;T;T
Sift4G	Uncertain	0.0090	D;D;T;D;T;T
Polyphen		0.11	B;B;B;.;.;.
Vest4		0.19
MVP		0.067
MPC		0.46
ClinPred		0.21	T
GERP RS		-0.85
Varity_R		0.14
gMVP		0.13

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

LitVar

Other links and lift over

dbSNP: rs752097227; hg19: chrX-55185590;