10-14521925-T-G

Position:

• chr10-14521925-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_031453.4(FAM107B):​c.748A>C​(p.Lys250Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000752 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: FAM107B NM_031453.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.67

Genes affected

FAM107B (HGNC:23726): (family with sequence similarity 107 member B) Predicted to act upstream of or within sensory perception of sound. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22755364).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAM107B	NM_031453.4	c.748A>C	p.Lys250Gln	missense_variant	4/5	ENST00000181796.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAM107B	ENST00000181796.7	c.748A>C	p.Lys250Gln	missense_variant	4/5	2	NM_031453.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Dec 28, 2023

The c.748A>C (p.K250Q) alteration is located in exon 4 (coding exon 4) of the FAM107B gene. This alteration results from a A to C substitution at nucleotide position 748, causing the lysine (K) at amino acid position 250 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	Benign	0.071
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	26
DANN	Benign	0.97
DEOGEN2	Benign	0.0085	T;T;.;T;T;T;T;T;T;T;T;.;T;T;T;.;T;T;T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	.;D;D;.;.;.;.;.;.;.;.;D;D;D;D;D;D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.23	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.40	N;N;.;N;N;N;N;N;N;N;N;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.2	N;.;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.37	T;.;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.43	T;T;T;T;T;T;T;T;T;T;T;.;.;.;.;.;T;.;.
Polyphen		0.043	B;B;D;B;B;B;B;B;B;B;B;.;.;.;.;.;.;.;.
Vest4		0.43
MutPred		0.43		Loss of ubiquitination at K75 (P = 0.0244);Loss of ubiquitination at K75 (P = 0.0244);.;Loss of ubiquitination at K75 (P = 0.0244);Loss of ubiquitination at K75 (P = 0.0244);Loss of ubiquitination at K75 (P = 0.0244);Loss of ubiquitination at K75 (P = 0.0244);Loss of ubiquitination at K75 (P = 0.0244);Loss of ubiquitination at K75 (P = 0.0244);Loss of ubiquitination at K75 (P = 0.0244);Loss of ubiquitination at K75 (P = 0.0244);Loss of ubiquitination at K75 (P = 0.0244);Loss of ubiquitination at K75 (P = 0.0244);Loss of ubiquitination at K75 (P = 0.0244);Loss of ubiquitination at K75 (P = 0.0244);Loss of ubiquitination at K75 (P = 0.0244);Loss of ubiquitination at K75 (P = 0.0244);Loss of ubiquitination at K75 (P = 0.0244);Loss of ubiquitination at K75 (P = 0.0244);
MVP		0.30
MPC		0.61
ClinPred		0.81	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.087

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: rs1845684918; hg19: chr10-14563924;