17-44354431-C-T

Position:

• chr17-44354431-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198475.3(FAM171A2):​c.1783G>A​(p.Glu595Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000102 in 984,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 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: 0.0000010 (0 hom.)
• Consequence: FAM171A2 NM_198475.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.02

Genes affected

FAM171A2 (HGNC:30480): (family with sequence similarity 171 member A2) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.097738415).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM171A2	NM_198475.3	c.1783G>A	p.Glu595Lys	missense_variant	8/8	ENST00000293443.12	NP_940877.2
FAM171A2	XM_017024490.2	c.1231G>A	p.Glu411Lys	missense_variant	6/6		XP_016879979.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM171A2	ENST00000293443.12	c.1783G>A	p.Glu595Lys	missense_variant	8/8	1	NM_198475.3	ENSP00000293443.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000102 AC: 1 AN: 984954 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 467048

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: 0.0000527

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.000710 AC: 2

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

Oct 06, 2023

The c.1783G>A (p.E595K) alteration is located in exon 8 (coding exon 8) of the FAM171A2 gene. This alteration results from a G to A substitution at nucleotide position 1783, causing the glutamic acid (E) at amino acid position 595 to be replaced by a lysine (K). 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	0.22
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0057	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.49	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.098	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.035
Sift	Benign	0.20	T
Sift4G	Benign	0.59	T
Polyphen		0.88	P
Vest4		0.093
MutPred		0.41		Gain of glycosylation at E595 (P = 0.0054);
MVP		0.030
ClinPred		0.29	T
GERP RS		2.9
Varity_R		0.12
gMVP		0.23

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: rs752086752; hg19: chr17-42431799;