5-74781699-T-C

Position:

• chr5-74781699-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001376049.1(FAM169A):​c.1774A>G​(p.Ile592Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: 0.0000014 (0 hom.)
• Consequence: FAM169A NM_001376049.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0800

Genes affected

FAM169A (HGNC:29138): (family with sequence similarity 169 member A) Predicted to be located in nuclear inner membrane. [provided by Alliance of Genome Resources, Apr 2022]

FAM169A (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.038590938).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM169A	NM_001376049.1	c.1774A>G	p.Ile592Val	missense_variant	13/13	ENST00000687041.1	NP_001362978.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM169A	ENST00000687041.1	c.1774A>G	p.Ile592Val	missense_variant	13/13		NM_001376049.1	ENSP00000508577.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461852 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727224

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.00000828 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

Dec 19, 2022

The c.1774A>G (p.I592V) alteration is located in exon 13 (coding exon 12) of the FAM169A gene. This alteration results from a A to G substitution at nucleotide position 1774, causing the isoleucine (I) at amino acid position 592 to be replaced by a valine (V). 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	0.082
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	12
DANN	Benign	0.97
DEOGEN2	Benign	0.022	T;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.039	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.26	N;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.050	N;N
REVEL	Benign	0.025
Sift	Benign	0.23	T;T
Sift4G	Benign	0.81	T;T
Polyphen		0.049	B;B
Vest4		0.076
MVP		0.043
MPC		0.20
ClinPred		0.083	T
GERP RS		3.0
Varity_R		0.037
gMVP		0.069

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: rs370884414; hg19: chr5-74077524;