NM_001012446.4:c.1154G>A

Variant names:

• chr9-35818907-C-T
• rs1244397573
• NM_001012446.4:c.1154G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001012446.4(FAM221B):​c.1154G>A​(p.Arg385Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000129 in 1,399,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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: 0.000013 (0 hom.)
• Consequence: FAM221B NM_001012446.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.10
• Publications: 0 publications found

Genes affected

FAM221B (HGNC:30762): (family with sequence similarity 221 member B)

ENSG00000285645 (HGNC:):

TMEM8B (HGNC:21427): (transmembrane protein 8B) Involved in cell-matrix adhesion. Located in cell surface and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.044181645).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001012446.4. 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
	FAM221B	NM_001012446.4	MANE Select	c.1154G>A	p.Arg385Gln	missense	Exon 6 of 7	NP_001012448.2	A6H8Z2-1
	FAM221B	NR_052026.2		n.1615G>A		non_coding_transcript_exon	Exon 7 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM221B	ENST00000423537.7	TSL:1 MANE Select	c.1154G>A	p.Arg385Gln	missense	Exon 6 of 7	ENSP00000415299.2	A6H8Z2-1
	FAM221B	ENST00000388950.8	TSL:1	n.*322G>A		non_coding_transcript_exon	Exon 7 of 8	ENSP00000373602.4	A6H8Z2-3
	ENSG00000285645	ENST00000650284.1		n.167G>A		non_coding_transcript_exon	Exon 5 of 10	ENSP00000498023.1	A0A3B3IU11

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000127 AC: 2 AN: 157574 AF XY: 0.0000240

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000129 AC: 18 AN: 1399626 Hom.: 0 Cov.: 32 AF XY: 0.0000188 AC XY: 13 AN XY: 690312

African (AFR) AF: 0.00 AC: 0 AN: 31596

American (AMR) AF: 0.0000560 AC: 2 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25180

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35738

South Asian (SAS) AF: 0.000139 AC: 11 AN: 79232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00000371 AC: 4 AN: 1079042

Other (OTH) AF: 0.00 AC: 0 AN: 58078

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	15
DANN	Benign	0.93
DEOGEN2	Benign	0.00096	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.36	N
PhyloP100		1.1
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.0070
Sift	Benign	0.29	T
Sift4G	Benign	0.41	T
Polyphen		0.040	B
Vest4		0.17
MutPred		0.23		Loss of MoRF binding (P = 0.0209)
MVP		0.055
MPC		0.087
ClinPred		0.052	T
GERP RS		0.90
Varity_R		0.032
gMVP		0.12
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1244397573; hg19: chr9-35818904; COSMIC: COSV52413893; COSMIC: COSV52413893;