rs2277944

Variant names:

• chr5-170106236-G-A
• rs2277944
• NM_012188.5:c.279G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_012188.5(FOXI1):​c.279G>A​(p.Arg93Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 1,577,604 control chromosomes in the GnomAD database, including 36,868 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (8264 hom., cov: 32)
  • Exomes 𝑓: 0.18 (28604 hom.)
• Consequence: FOXI1 NM_012188.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.39
• Publications: 15 publications found

Genes affected

FOXI1 (HGNC:3815): (forkhead box I1) This gene belongs to the forkhead family of transcription factors, which is characterized by a distinct forkhead domain. This gene may play an important role in the development of the cochlea and vestibulum, as well as in embryogenesis. The encoded protein has been found to be required for the transcription of four subunits of a proton pump found in the inner ear, the kidney, and the epididymis. Mutations in this gene have been associated with deafness, autosomal recessive 4. [provided by RefSeq, Jan 2017]

FOXI1 Gene-Disease associations (from GenCC):

• autosomal recessive distal renal tubular acidosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Pendred syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss disorder

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 4

  Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• enlarged vestibular aqueduct syndrome

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 5-170106236-G-A is Benign according to our data. Variant chr5-170106236-G-A is described in ClinVar as Benign. ClinVar VariationId is 352702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.39 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.526 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012188.5. 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
	FOXI1	NM_012188.5	MANE Select	c.279G>A	p.Arg93Arg	synonymous	Exon 1 of 2	NP_036320.2
	FOXI1	NM_144769.4		c.279G>A	p.Arg93Arg	synonymous	Exon 1 of 2	NP_658982.1	Q12951-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXI1	ENST00000306268.8	TSL:1 MANE Select	c.279G>A	p.Arg93Arg	synonymous	Exon 1 of 2	ENSP00000304286.5	Q12951-1
	FOXI1	ENST00000449804.4	TSL:1	c.279G>A	p.Arg93Arg	synonymous	Exon 1 of 2	ENSP00000415483.2	Q12951-2

Frequencies

GnomAD3 genomes AF: 0.286 AC: 43513 AN: 151974 Hom.: 8239 Cov.: 32

Gnomad AFR AF: 0.532

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.193

Gnomad EAS AF: 0.471

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.271

GnomAD2 exomes AF: 0.231 AC: 43364 AN: 187600 AF XY: 0.224

Gnomad AFR exome AF: 0.550

Gnomad AMR exome AF: 0.223

Gnomad ASJ exome AF: 0.191

Gnomad EAS exome AF: 0.476

Gnomad FIN exome AF: 0.196

Gnomad NFE exome AF: 0.165

Gnomad OTH exome AF: 0.203

GnomAD4 exome AF: 0.184 AC: 262761 AN: 1425512 Hom.: 28604 Cov.: 35 AF XY: 0.185 AC XY: 130440 AN XY: 706096

African (AFR) AF: 0.551 AC: 17844 AN: 32394

American (AMR) AF: 0.219 AC: 8702 AN: 39668

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 4726 AN: 25430

East Asian (EAS) AF: 0.458 AC: 17061 AN: 37242

South Asian (SAS) AF: 0.222 AC: 18237 AN: 82060

European-Finnish (FIN) AF: 0.189 AC: 9563 AN: 50550

Middle Eastern (MID) AF: 0.172 AC: 983 AN: 5714

European-Non Finnish (NFE) AF: 0.159 AC: 173520 AN: 1093480

Other (OTH) AF: 0.206 AC: 12125 AN: 58974

GnomAD4 genome AF: 0.287 AC: 43587 AN: 152092 Hom.: 8264 Cov.: 32 AF XY: 0.287 AC XY: 21336 AN XY: 74364

African (AFR) AF: 0.532 AC: 22065 AN: 41462

American (AMR) AF: 0.224 AC: 3434 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 670 AN: 3472

East Asian (EAS) AF: 0.472 AC: 2420 AN: 5130

South Asian (SAS) AF: 0.245 AC: 1182 AN: 4824

European-Finnish (FIN) AF: 0.195 AC: 2070 AN: 10606

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.161 AC: 10952 AN: 67984

Other (OTH) AF: 0.277 AC: 584 AN: 2110

Alfa AF: 0.206 Hom.: 2361

Bravo AF: 0.300

Asia WGS AF: 0.347 AC: 1206 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	4.2
DANN	Benign	0.34
PhyloP100		2.4
PromoterAI		-0.034	Neutral
Mutation Taster		=93/7	polymorphism (auto)

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: rs2277944; hg19: chr5-169533240; COSMIC: COSV60387898;