5-154011276-G-C

Variant names:

• chr5-154011276-G-C
• NM_018691.4:c.958C>G

Variant summary

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

The NM_018691.4(FAM114A2):​c.958C>G​(p.Leu320Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,202 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FAM114A2 NM_018691.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.58

Genes affected

FAM114A2 (HGNC:1333): (family with sequence similarity 114 member A2)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM114A2	NM_018691.4	c.958C>G	p.Leu320Val	missense_variant	Exon 9 of 14	ENST00000351797.9	NP_061161.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM114A2	ENST00000351797.9	c.958C>G	p.Leu320Val	missense_variant	Exon 9 of 14	1	NM_018691.4	ENSP00000341597.4
FAM114A2	ENST00000520667.5	c.958C>G	p.Leu320Val	missense_variant	Exon 10 of 15	1		ENSP00000430384.1
FAM114A2	ENST00000522858.5	c.958C>G	p.Leu320Val	missense_variant	Exon 9 of 14	1		ENSP00000430489.1
FAM114A2	ENST00000520313.5	c.748C>G	p.Leu250Val	missense_variant	Exon 8 of 13	2		ENSP00000429088.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460202 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726394

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: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 9.00e-7

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

May 30, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.958C>G (p.L320V) alteration is located in exon 9 (coding exon 8) of the FAM114A2 gene. This alteration results from a C to G substitution at nucleotide position 958, causing the leucine (L) at amino acid position 320 to be replaced by a valine (V). 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	0.21
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;T;T;T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.92	.;.;D;D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.74	D;D;D;D
MetaSVM	Benign	-0.75	T
MutationAssessor	Pathogenic	3.0	M;M;M;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.7	D;D;D;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.72
MutPred		0.61		Loss of catalytic residue at L320 (P = 0.0195);Loss of catalytic residue at L320 (P = 0.0195);Loss of catalytic residue at L320 (P = 0.0195);.;
MVP		0.24
MPC		0.18
ClinPred		0.98	D
GERP RS		3.8
Varity_R		0.37
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.21		Position offset: -35

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-153390836;