19-35225196-C-T

Variant names:

• chr19-35225196-C-T
• rs1298961456
• NM_152481.2:c.739G>A

Variant summary

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

The NM_152481.2(FAM187B):​c.739G>A​(p.Ala247Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000148 in 1,350,528 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 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: 0.0000015 (0 hom.)
• Consequence: FAM187B NM_152481.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.543

Genes affected

FAM187B (HGNC:26366): (family with sequence similarity 187 member B) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

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
FAM187B	NM_152481.2	c.739G>A	p.Ala247Thr	missense_variant	Exon 2 of 2	ENST00000324675.4	NP_689694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM187B	ENST00000324675.4	c.739G>A	p.Ala247Thr	missense_variant	Exon 2 of 2	1	NM_152481.2	ENSP00000323355.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000148 AC: 2 AN: 1350528 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 659264

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: 0.00

Gnomad4 NFE exome AF: 0.00000189

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

Oct 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.739G>A (p.A247T) alteration is located in exon 2 (coding exon 2) of the FAM187B gene. This alteration results from a G to A substitution at nucleotide position 739, causing the alanine (A) at amino acid position 247 to be replaced by a threonine (T). 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	0.16
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0067	T
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.8	L
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.15
Sift	Benign	0.092	T
Sift4G	Benign	0.12	T
Polyphen		0.99	D
Vest4		0.22
MutPred		0.78		Gain of relative solvent accessibility (P = 0.0023);
MVP		0.52
MPC		0.82
ClinPred		0.34	T
GERP RS		1.8
Varity_R		0.063
gMVP		0.48

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: rs1298961456; hg19: chr19-35716099;