9-35819374-C-T

Variant names:

• chr9-35819374-C-T
• rs115621078
• NM_001012446.4:c.874G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001012446.4(FAM221B):​c.874G>A​(p.Val292Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00188 in 1,551,648 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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. V292L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0094 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (17 hom.)
• Consequence: FAM221B NM_001012446.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0190
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025111735).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00943 (1436/152300) while in subpopulation AFR AF = 0.033 (1370/41552). AF 95% confidence interval is 0.0315. There are 12 homozygotes in GnomAd4. There are 699 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

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.874G>A	p.Val292Ile	missense	Exon 5 of 7	NP_001012448.2	A6H8Z2-1
	FAM221B	NR_052026.2		n.1335G>A		non_coding_transcript_exon	Exon 6 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM221B	ENST00000423537.7	TSL:1 MANE Select	c.874G>A	p.Val292Ile	missense	Exon 5 of 7	ENSP00000415299.2	A6H8Z2-1
	FAM221B	ENST00000377984.2	TSL:1	c.874G>A	p.Val292Ile	missense	Exon 6 of 6	ENSP00000367222.2	F8W8N9
	FAM221B	ENST00000388950.8	TSL:1	n.*42G>A		non_coding_transcript_exon	Exon 6 of 8	ENSP00000373602.4	A6H8Z2-3

Frequencies

GnomAD3 genomes AF: 0.00944 AC: 1437 AN: 152182 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0331

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00862

GnomAD2 exomes AF: 0.00208 AC: 325 AN: 156278 AF XY: 0.00165

Gnomad AFR exome AF: 0.0348

Gnomad AMR exome AF: 0.00166

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000497

Gnomad OTH exome AF: 0.000911

GnomAD4 exome AF: 0.00106 AC: 1485 AN: 1399348 Hom.: 17 Cov.: 32 AF XY: 0.000894 AC XY: 617 AN XY: 690192

African (AFR) AF: 0.0370 AC: 1169 AN: 31596

American (AMR) AF: 0.00162 AC: 58 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25178

East Asian (EAS) AF: 0.00 AC: 0 AN: 35740

South Asian (SAS) AF: 0.0000631 AC: 5 AN: 79234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49286

Middle Eastern (MID) AF: 0.00228 AC: 13 AN: 5698

European-Non Finnish (NFE) AF: 0.0000834 AC: 90 AN: 1078916

Other (OTH) AF: 0.00259 AC: 150 AN: 57998

GnomAD4 genome AF: 0.00943 AC: 1436 AN: 152300 Hom.: 12 Cov.: 32 AF XY: 0.00939 AC XY: 699 AN XY: 74478

African (AFR) AF: 0.0330 AC: 1370 AN: 41552

American (AMR) AF: 0.00288 AC: 44 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68036

Other (OTH) AF: 0.00853 AC: 18 AN: 2110

Alfa AF: 0.00234 Hom.: 3

Bravo AF: 0.0111

ESP6500AA AF: 0.0354 AC: 49

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00293 AC: 76

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0053	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.019
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.016
Sift	Benign	0.070	T
Sift4G	Benign	0.26	T
Polyphen		0.51	P
Vest4		0.15
MVP		0.030
MPC		0.10
ClinPred		0.0063	T
GERP RS		1.8
Varity_R		0.030
gMVP		0.21
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs115621078; hg19: chr9-35819371;