rs77136537

Variant names:

• chr5-170107990-G-A
• rs77136537
• NM_012188.5:c.575-59G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-170107990-G-A
• chr5-170107990-G-C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_012188.5(FOXI1):​c.575-59G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00973 in 1,347,514 control chromosomes in the GnomAD database, including 164 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0098 (18 hom., cov: 33)
  • Exomes 𝑓: 0.0097 (146 hom.)
• Consequence: FOXI1 NM_012188.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.298
• Publications: 2 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 5-170107990-G-A is Benign according to our data. Variant chr5-170107990-G-A is described in ClinVar as Benign. ClinVar VariationId is 1282730.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00976 (1487/152302) while in subpopulation SAS AF = 0.0297 (143/4818). AF 95% confidence interval is 0.0257. There are 18 homozygotes in GnomAd4. There are 890 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 AR,Unknown gene

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.575-59G>A		intron	N/A	NP_036320.2
	FOXI1	NM_144769.4		c.575-344G>A		intron	N/A	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.575-59G>A		intron	N/A	ENSP00000304286.5	Q12951-1
	FOXI1	ENST00000449804.4	TSL:1	c.575-344G>A		intron	N/A	ENSP00000415483.2	Q12951-2

Frequencies

GnomAD3 genomes AF: 0.00978 AC: 1488 AN: 152184 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.0119

Gnomad SAS AF: 0.0299

Gnomad FIN AF: 0.0444

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00816

Gnomad OTH AF: 0.00526

GnomAD4 exome AF: 0.00972 AC: 11621 AN: 1195212 Hom.: 146 AF XY: 0.0103 AC XY: 6239 AN XY: 607794

African (AFR) AF: 0.000672 AC: 19 AN: 28254

American (AMR) AF: 0.0175 AC: 770 AN: 44002

Ashkenazi Jewish (ASJ) AF: 0.00944 AC: 230 AN: 24352

East Asian (EAS) AF: 0.0113 AC: 436 AN: 38440

South Asian (SAS) AF: 0.0260 AC: 2088 AN: 80290

European-Finnish (FIN) AF: 0.0471 AC: 2489 AN: 52798

Middle Eastern (MID) AF: 0.00247 AC: 13 AN: 5270

European-Non Finnish (NFE) AF: 0.00588 AC: 5120 AN: 870130

Other (OTH) AF: 0.00882 AC: 456 AN: 51676

GnomAD4 genome AF: 0.00976 AC: 1487 AN: 152302 Hom.: 18 Cov.: 33 AF XY: 0.0120 AC XY: 890 AN XY: 74472

African (AFR) AF: 0.000818 AC: 34 AN: 41566

American (AMR) AF: 0.0111 AC: 170 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00893 AC: 31 AN: 3472

East Asian (EAS) AF: 0.0120 AC: 62 AN: 5182

South Asian (SAS) AF: 0.0297 AC: 143 AN: 4818

European-Finnish (FIN) AF: 0.0444 AC: 471 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00816 AC: 555 AN: 68028

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00793 Hom.: 4

Bravo AF: 0.00595

Asia WGS AF: 0.0220 AC: 76 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.84
DANN	Benign	0.48
PhyloP100		-0.30
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: rs77136537; hg19: chr5-169534994; COSMIC: COSV60389644;