5-74796041-C-G

Variant names:

• chr5-74796041-C-G
• rs539857601
• NM_001376049.1:c.1249G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001376049.1(FAM169A):​c.1249G>C​(p.Asp417His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign 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. D417N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FAM169A NM_001376049.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.52
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21231997).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001376049.1. 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
	FAM169A	NM_001376049.1	MANE Select	c.1249G>C	p.Asp417His	missense	Exon 11 of 13	NP_001362978.1	Q9Y6X4-1
	FAM169A	NM_001376050.1		c.1249G>C	p.Asp417His	missense	Exon 11 of 13	NP_001362979.1	Q9Y6X4-1
	FAM169A	NM_001376051.1		c.1249G>C	p.Asp417His	missense	Exon 11 of 13	NP_001362980.1	Q9Y6X4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM169A	ENST00000687041.1	MANE Select	c.1249G>C	p.Asp417His	missense	Exon 11 of 13	ENSP00000508577.1	Q9Y6X4-1
	FAM169A	ENST00000389156.9	TSL:1	c.1249G>C	p.Asp417His	missense	Exon 11 of 13	ENSP00000373808.4	Q9Y6X4-1
	FAM169A	ENST00000510609.5	TSL:1	n.*693G>C		non_coding_transcript_exon	Exon 10 of 12	ENSP00000423905.1	Q9Y6X4-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460522 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726414

African (AFR) AF: 0.00 AC: 0 AN: 33404

American (AMR) AF: 0.00 AC: 0 AN: 44420

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 85648

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111746

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.084	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		2.5
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.14
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.013	D
Polyphen		0.98	D
Vest4		0.25
MutPred		0.19		Gain of helix (P = 0.0696)
MVP		0.12
MPC		0.81
ClinPred		0.88	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.057
gMVP		0.14
Mutation Taster		=93/7	polymorphism

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: rs539857601; hg19: chr5-74091866;