8-138151387-C-T

Position:

• chr8-138151387-C-T

Variant summary

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

The NM_015912.4(FAM135B):​c.3088G>A​(p.Val1030Ile) 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. 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: 33)
• Consequence: FAM135B NM_015912.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.10

Genes affected

FAM135B (HGNC:28029): (family with sequence similarity 135 member B) Predicted to be involved in cellular lipid metabolic process. [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=0.11579496).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAM135B	NM_015912.4	c.3088G>A	p.Val1030Ile	missense_variant	13/20	ENST00000395297.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAM135B	ENST00000395297.6	c.3088G>A	p.Val1030Ile	missense_variant	13/20	5	NM_015912.4	P1
FAM135B	ENST00000467365.2	n.1018G>A		non_coding_transcript_exon_variant	1/4	1
FAM135B	ENST00000482951.6	c.*3034G>A		3_prime_UTR_variant, NMD_transcript_variant	14/21	1
FAM135B	ENST00000276737.10	c.3088G>A	p.Val1030Ile	missense_variant, NMD_transcript_variant	13/20	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250394 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135336

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

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 08, 2023

The c.3088G>A (p.V1030I) alteration is located in exon 13 (coding exon 12) of the FAM135B gene. This alteration results from a G to A substitution at nucleotide position 3088, causing the valine (V) at amino acid position 1030 to be replaced by an isoleucine (I). 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	0.091
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.049	T
Eigen	Benign	0.095
Eigen_PC	Benign	0.092
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	0.75	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.093
Sift	Benign	0.44	T
Sift4G	Benign	0.97	T
Polyphen		0.91	P
Vest4		0.082
MutPred		0.23		Gain of catalytic residue at V1031 (P = 0.133);
MVP		0.068
MPC		0.058
ClinPred		0.63	D
GERP RS		4.5
Varity_R		0.045
gMVP		0.29

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: rs778107331; hg19: chr8-139163630;