6-70528402-A-G

Variant names:

• chr6-70528402-A-G
• rs2747701
• NM_001162529.3:c.3725A>G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001162529.3(FAM135A):​c.3725A>G​(p.Asp1242Gly) variant causes a missense change. The variant allele was found at a frequency of 0.451 in 1,612,320 control chromosomes in the GnomAD database, including 172,014 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.35 (11506 hom., cov: 32)
  • Exomes 𝑓: 0.46 (160508 hom.)
• Consequence: FAM135A NM_001162529.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.19

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.6963482E-4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.514 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM135A	NM_001162529.3	c.3725A>G	p.Asp1242Gly	missense_variant	Exon 16 of 22	ENST00000418814.7	NP_001156001.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM135A	ENST00000418814.7	c.3725A>G	p.Asp1242Gly	missense_variant	Exon 16 of 22	5	NM_001162529.3	ENSP00000410768.2

Frequencies

GnomAD3 genomes AF: 0.348 AC: 52893 AN: 151890 Hom.: 11512 Cov.: 32

Gnomad AFR AF: 0.0864

Gnomad AMI AF: 0.566

Gnomad AMR AF: 0.309

Gnomad ASJ AF: 0.465

Gnomad EAS AF: 0.530

Gnomad SAS AF: 0.481

Gnomad FIN AF: 0.407

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.474

Gnomad OTH AF: 0.375

GnomAD3 exomes AF: 0.413 AC: 103450 AN: 250500 Hom.: 23346 AF XY: 0.430 AC XY: 58256 AN XY: 135382

Gnomad AFR exome AF: 0.0753

Gnomad AMR exome AF: 0.245

Gnomad ASJ exome AF: 0.470

Gnomad EAS exome AF: 0.531

Gnomad SAS exome AF: 0.474

Gnomad FIN exome AF: 0.412

Gnomad NFE exome AF: 0.471

Gnomad OTH exome AF: 0.426

GnomAD4 exome AF: 0.462 AC: 674246 AN: 1460312 Hom.: 160508 Cov.: 39 AF XY: 0.464 AC XY: 336863 AN XY: 726444

Gnomad4 AFR exome AF: 0.0721

Gnomad4 AMR exome AF: 0.252

Gnomad4 ASJ exome AF: 0.468

Gnomad4 EAS exome AF: 0.556

Gnomad4 SAS exome AF: 0.477

Gnomad4 FIN exome AF: 0.418

Gnomad4 NFE exome AF: 0.480

Gnomad4 OTH exome AF: 0.444

GnomAD4 genome AF: 0.348 AC: 52882 AN: 152008 Hom.: 11506 Cov.: 32 AF XY: 0.347 AC XY: 25807 AN XY: 74280

Gnomad4 AFR AF: 0.0861

Gnomad4 AMR AF: 0.309

Gnomad4 ASJ AF: 0.465

Gnomad4 EAS AF: 0.531

Gnomad4 SAS AF: 0.482

Gnomad4 FIN AF: 0.407

Gnomad4 NFE AF: 0.474

Gnomad4 OTH AF: 0.368

Alfa AF: 0.458 Hom.: 40671

Bravo AF: 0.329

TwinsUK AF: 0.488 AC: 1809

ALSPAC AF: 0.481 AC: 1852

ESP6500AA AF: 0.0865 AC: 381

ESP6500EA AF: 0.481 AC: 4138

ExAC AF: 0.415 AC: 50351

Asia WGS AF: 0.398 AC: 1383 AN: 3478

EpiCase AF: 0.486

EpiControl AF: 0.485

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T;T;.;.;T;.
Eigen	Benign	-0.099
Eigen_PC	Benign	-0.054
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.81	.;T;T;T;T;T
MetaRNN	Benign	0.00017	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;.;.;.;M;M
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-4.3	D;D;D;D;.;D
REVEL	Benign	0.15
Sift	Uncertain	0.018	D;T;D;D;.;D
Sift4G	Uncertain	0.0050	D;T;D;D;D;D
Polyphen		0.067	B;B;B;B;B;B
Vest4		0.15
MPC		0.25
ClinPred		0.049	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.35
gMVP		0.50

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: rs2747701; hg19: chr6-71238105; COSMIC: COSV52047515; COSMIC: COSV52047515;