22-38605295-T-A

Variant names:

• chr22-38605295-T-A
• rs560936960
• NM_001013647.2:c.1180A>T

Variant summary

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

The NM_001013647.2(FAM227A):​c.1180A>T​(p.Ile394Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000258 in 1,551,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/19 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. I394V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FAM227A NM_001013647.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.800
• Publications: 0 publications found

Genes affected

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

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=0.12847057).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001013647.2. 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
	FAM227A	NM_001013647.2	MANE Select	c.1180A>T	p.Ile394Leu	missense	Exon 13 of 17	NP_001013669.1	F5H4B4-1
	FAM227A	NM_001384270.1		c.913A>T	p.Ile305Leu	missense	Exon 13 of 17	NP_001371199.1
	FAM227A	NM_001291030.2		c.901A>T	p.Ile301Leu	missense	Exon 13 of 17	NP_001277959.1	F5H4B4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM227A	ENST00000535113.7	TSL:5 MANE Select	c.1180A>T	p.Ile394Leu	missense	Exon 13 of 17	ENSP00000445093.1	F5H4B4-1
	FAM227A	ENST00000355830.11	TSL:5	c.1180A>T	p.Ile394Leu	missense	Exon 13 of 19	ENSP00000348086.7	A0A0A0MRD0
	FAM227A	ENST00000540952.6	TSL:5	c.1180A>T	p.Ile394Leu	missense	Exon 13 of 17	ENSP00000493504.1	A0A2R8YCE3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1399008 Hom.: 0 Cov.: 28 AF XY: 0.00000290 AC XY: 2 AN XY: 690074

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31574

American (AMR) AF: 0.0000280 AC: 1 AN: 35706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25172

East Asian (EAS) AF: 0.00 AC: 0 AN: 35734

South Asian (SAS) AF: 0.00 AC: 0 AN: 79212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49540

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078206

Other (OTH) AF: 0.0000172 AC: 1 AN: 58162

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74350

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.0048	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.80
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.068
Sift	Benign	0.25	T
Sift4G	Uncertain	0.033	D
Polyphen		0.89	P
Vest4		0.22
MutPred		0.23		Loss of loop (P = 0.0022)
MVP		0.030
ClinPred		0.49	T
GERP RS		1.2
Varity_R		0.11
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs560936960; hg19: chr22-39001300;