5-93881482-T-G

Variant summary

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

The NM_032042.6(FAM172A):c.774A>C(p.Gln258His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000549 in 1,458,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 0.0000055 (0 hom.)
• Consequence: FAM172A NM_032042.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0170

Genes affected

FAM172A (HGNC:25365): (ARB2 cotranscriptional regulator A) Predicted to contribute to siRNA binding activity. Predicted to be involved in heterochromatin assembly by small RNA; neural crest cell development; and regulation of alternative mRNA splicing, via spliceosome. Located in endoplasmic reticulum. [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=0.13425887).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAM172A	NM_032042.6	c.774A>C	p.Gln258His	missense_variant	7/11	ENST00000395965.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAM172A	ENST00000395965.8	c.774A>C	p.Gln258His	missense_variant	7/11	1	NM_032042.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000549 AC: 8 AN: 1458014 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725342

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: 0.00000721

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Mar 23, 2023

The c.774A>C (p.Q258H) alteration is located in exon 7 (coding exon 6) of the FAM172A gene. This alteration results from a A to C substitution at nucleotide position 774, causing the glutamine (Q) at amino acid position 258 to be replaced by a histidine (H). 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	0.21
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	14
Dann	Benign	0.91
DEOGEN2	Benign	0.022	T;.;.;.
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.78	T;T;T;T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.76	N;.;.;.
MutationTaster	Benign	0.63	D;D;D;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.55	N;N;N;N
REVEL	Benign	0.045
Sift	Benign	0.19	T;T;T;T
Sift4G	Benign	0.16	T;T;T;T
Polyphen		0.0	B;.;B;.
Vest4		0.33
MutPred		0.42		Loss of MoRF binding (P = 0.1016);.;.;.;
MVP		0.27
MPC		0.080
ClinPred		0.18	T
GERP RS		-0.89
Varity_R		0.060
gMVP		0.37

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-93217188;