8-138148544-C-A

Variant names:

• chr8-138148544-C-A
• rs35765793
• NM_015912.4:c.3424G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015912.4(FAM135B):​c.3424G>T​(p.Val1142Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1142I) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FAM135B NM_015912.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.12
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.759

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015912.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM135B	NM_015912.4	MANE Select	c.3424G>T	p.Val1142Phe	missense	Exon 14 of 20	NP_056996.2	Q49AJ0-1
	FAM135B	NM_001362965.2		c.3424G>T	p.Val1142Phe	missense	Exon 14 of 20	NP_001349894.1	Q49AJ0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM135B	ENST00000395297.6	TSL:5 MANE Select	c.3424G>T	p.Val1142Phe	missense	Exon 14 of 20	ENSP00000378710.1	Q49AJ0-1
	FAM135B	ENST00000467365.2	TSL:1	n.1250G>T		non_coding_transcript_exon	Exon 2 of 4
	FAM135B	ENST00000482951.6	TSL:1	n.*3370G>T		non_coding_transcript_exon	Exon 15 of 21	ENSP00000429874.1	E5RH68

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461728 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727174

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111942

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.072	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.82	L
PhyloP100		6.1
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.62		Loss of stability (P = 0.0871)
MVP		0.14
MPC		2.3
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.79
gMVP		0.95
Mutation Taster		=19/81	disease causing

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

Other links and lift over

dbSNP: rs35765793; hg19: chr8-139160787;