22-38605342-T-C

Variant names:

• chr22-38605342-T-C
• rs1358337434
• NM_001013647.2:c.1133A>G

Variant summary

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

The NM_001013647.2(FAM227A):​c.1133A>G​(p.His378Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,388,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/17 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: 0.000014 (0 hom.)
• Consequence: FAM227A NM_001013647.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.17

Genes affected

FAM227A (HGNC:44197): (family with sequence similarity 227 member A)

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=0.06728399).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM227A	NM_001013647.2	c.1133A>G	p.His378Arg	missense_variant	Exon 13 of 17	ENST00000535113.7	NP_001013669.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM227A	ENST00000535113.7	c.1133A>G	p.His378Arg	missense_variant	Exon 13 of 17	5	NM_001013647.2	ENSP00000445093.1
FAM227A	ENST00000355830.11	c.1133A>G	p.His378Arg	missense_variant	Exon 13 of 19	5		ENSP00000348086.7
FAM227A	ENST00000540952.6	c.1133A>G	p.His378Arg	missense_variant	Exon 13 of 17	5		ENSP00000493504.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000137 AC: 19 AN: 1388348 Hom.: 0 Cov.: 26 AF XY: 0.0000131 AC XY: 9 AN XY: 685472

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: 0.0000159

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000555 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1133A>G (p.H378R) alteration is located in exon 13 (coding exon 12) of the FAM227A gene. This alteration results from a A to G substitution at nucleotide position 1133, causing the histidine (H) at amino acid position 378 to be replaced by an arginine (R). 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	0.068
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.0080
DANN	Benign	0.20
DEOGEN2	Benign	0.0023	T;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0091	N
LIST_S2	Benign	0.42	T;.;T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.067	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.44	N;N;.
REVEL	Benign	0.012
Sift	Benign	0.57	T;T;.
Sift4G	Uncertain	0.047	D;D;.
Polyphen		0.0050	B;.;.
Vest4		0.035
MVP		0.014
ClinPred		0.049	T
GERP RS		-3.3
Varity_R		0.038

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: rs1358337434; hg19: chr22-39001347;