rs748520978

chr6-70477264-C-Gchr6-70477264-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM4 BP6

The NM_001162529.3(FAM135A):c.474C>G(p.Tyr158Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FAM135A NM_001162529.3 stop_gained
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.157

Genes affected

FAM135A (HGNC:21084): (family with sequence similarity 135 member A) 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_001162529.3 Downstream stopcodon found after 1653 codons.
• BP6: Variant 6-70477264-C-G is Benign according to our data. Variant chr6-70477264-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 254142.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAM135A	NM_001162529.3	c.474C>G	p.Tyr158Ter	stop_gained	8/22	ENST00000418814.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAM135A	ENST00000418814.7	c.474C>G	p.Tyr158Ter	stop_gained	8/22	5	NM_001162529.3	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Histiocytoid cardiomyopathy Benign:1

Likely benign, no assertion criteria provided

research

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

-

Subject had a likely pathogenic variant: a de novo nonsense variant in NDUFB11 (ENST00000276062.8: c.262C>T; p. (Arg88*)), a gene previously linked to Histiocytoid Cardiomyopathy. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
Cadd	Pathogenic	31
Dann	Uncertain	0.99
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.85	D
MutationTaster	Benign	1.0	A;A;A;A;A;A
Vest4		0.45
GERP RS		-4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs748520978; hg19: chr6-71186967;